Compositions containing 4,5,6,7-tetrahydrobenz[b]thien-4-yl-ureas or derivatives and methods of enhancing growth rate

ABSTRACT

This disclosure describes a novel method for improving feed efficiency and accelerating the growth rate of veterinary homothermic animals by administering to said animals a growth-promoting amount of a cycloalkano[b]thien-4-ylurea or thiourea.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of my abandoned applicationSer. No. 572,492, filed Apr. 25, 1975 which is a continuation-in-part ofmy abandoned application Ser. No. 436,826, filed Jan. 25, 1974.

SUMMARY OF THE INVENTION

This invention relates to a method for improving feed efficiency andenhancing the growth rate of veterinary homothermic animals such aspoultry, fur-bearing, and farm animals by orally or parenterallyadministering to said animals a growth-promoting amount ofcycloalkano[b]thien-4-ylurea or thiourea which may be represented byformula (I) below: ##STR1## wherein X is divalent oxygen or divalentsulfur; Y is a divalent moiety of the formulae: ##STR2## n is theinteger 1 or 2; R₁ is hydrogen or alkyl C₁ -C₄ ; R₃ is hydrogen, alkylC₁ -C₄, cycloalkyl C₃ -C₆, allyl, 2-propynyl, benzyl or β-phenylethyl;R₄ is hydrogen or alkyl C₁ -C₄ ; R₅ is hydrogen, chloro, bromo or iodo;R₆ is hydrogen or alkyl C₁ -C₄ ; R₂ is selected from the groupconsisting of the substitutents listed in Table I below:

                  TABLE I                                                         ______________________________________                                                 R.sub.2                                                              ______________________________________                                        hydrogen                                                                      alkyl C.sub.1 -C.sub.12                                                       cycloalkyl C.sub.3 -C.sub.6                                                   allyl                                                                         methallyl                                                                     2-butenyl                                                                     2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1 -C.sub.6                                                       allyloxy                                                                      methallyloxy                                                                  2-butenyloxy                                                                  methoxymethyl                                                                 OCH.sub.2COOH                                                                 phenoxy                                                                       benzyloxy                                                                     CH.sub.2CH.sub.2OH                                                            CH.sub.2CH.sub.2OCH.sub.3                                                     CH.sub.2CH.sub.2SCH.sub.3                                                     CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    CH.sub.2CO.sub.2 R                                                            NHCO.sub.2 R                                                                   ##STR3##                                                                      ##STR4##                                                                     CO.sub.2 C.sub.2 H.sub.5                                                       ##STR5##                                                                      ##STR6##                                                                      ##STR7##                                                                      ##STR8##                                                                      ##STR9##                                                                      ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                    ______________________________________                                    

wherein (in Table I) R is alkyl C₁ -C₄, m is 0, 1 or 2, and Q isselected from the group consisting of the substituents listed in TableII below:

                  TABLE II                                                        ______________________________________                                        m = 0            m = 1         m = 2                                          ______________________________________                                        2-methyl-4-bromo                                                                              hydrogen      hydrogen                                        3,4-methylenedioxy                                                                            4-chloro                                                      3- or 4-methoxy 4-methoxy                                                     4-ethoxy        3,4-methyl-                                                                   enedioxy                                                      4-chloro                                                                      4-butoxy                                                                      4-methylthio                                                                  2,4-dimethyl                                                                  2,5-dimethoxy                                                                 2,4-dichloro                                                                  4-nitro                                                                       ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-phenylpiperazino, 4-(4-methoxyphenyl)-piperazino,4-carbethoxypiperazino, 4-oxopiperazino, 1,2,3,4-tetrahydroquinolino andthe moiety of the formula: ##STR14##

DETAILED DESCRIPTION OF THE INVENTION

A preferred embodiment within the scope of the present invention may berepresented by the following formula: ##STR15## wherein X, Y, n, R₁, R₃,R₄, R₅ and R₆ are as hereinabove defined and R₂ is selected from thegroup consisting of the substituents listed in Table III below:

                  TABLE III                                                       ______________________________________                                                 R.sub.2                                                              ______________________________________                                        hydrogen                                                                      alkyl C.sub.1 -C.sub.8                                                        cycloalkyl C.sub.3 -C.sub.6                                                   allyl                                                                         methallyl                                                                     2-butenyl                                                                     2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1 -C.sub.6                                                       allyloxy                                                                      methallyloxy                                                                  2-butenyloxy                                                                  methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH.sub.2OH                                                            OCH.sub.2COOH                                                                 CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                   ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                     ##STR20##                                                                     ##STR21##                                                                     ##STR22##                                                                    benzyloxy                                                                     ______________________________________                                         7

wherein (in Table III) R and m are as hereinabove defined and Q isselected from the group consisting of the substituents listed in TableIV below:

                  TABLE IV                                                        ______________________________________                                        m = 0            m = 1         m = 2                                          ______________________________________                                        4-chloro        hydrogen      hydrogen                                        3,4-methylene-  4-methoxy                                                     dioxy                                                                         3- or 4-methoxy                                                               4-ethoxy                                                                      4-butoxy                                                                      4-methylthio                                                                  2,4-dimethyl                                                                  2,4-dichloro                                                                  4-nitro                                                                       2-methyl-4-bromo                                                              ______________________________________                                    

Another preferred embodiment within the scope of the present inventionmay be represented by the following formula: ##STR23## wherein X, Y, n,R₁, R₃, R₄ and R₅ are as hereinabove defined and R₂ is selected from thegroup consisting of the substituents listed in Table V below:

                  TABLE V                                                         ______________________________________                                                     R.sub.2                                                          ______________________________________                                                  hydrogen                                                                      alkyl C.sub.1 -C.sub.8                                                        cycloalkyl C.sub.3 -C.sub.4                                                   allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1 -C.sub.6                                                       methoxymethyl                                                                 phenoxy                                                                       4-methoxyphenyl                                                                ##STR24##                                                          ______________________________________                                    

Another preferred embodiment within the scope of the present inventionmay be represented by the following formula: ##STR25## wherein X and nare as hereinabove defined and R₂ and R₃ taken together with theassociated N(itrogen) is selected from the group consisting ofmorpholino, pyrrolidino, 4-phenylpiperazino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR26##

A most preferred embodiment within the scope of the present inventionmay be represented by the 4,5,6,7-tetrahydrobenzo[b]thien-4-ylureas andthioureas of the following formula: ##STR27## wherein X and Y are ashereinabove defined, R₂ is hydrogen, alkyl C₁ -C₈, allyl, alkoxy C₁ -C₄,2-propynyl methoxymethyl or hydroxy, and R₃ is hydrogen or alkyl C₁ -C₄.

Another most preferred embodiment within the scope of the presentinvention may be represented by the5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylureas and thioureas of thefollowing formula: ##STR28## wherein X and Y are as hereinabove defined,R₂ is hydrogen, alkyl C₁ -C₈, allyl, alkoxy C₁ -C₄, 2-propynyl,methoxymethyl or hydroxy, and R₃ is hydrogen or alkyl C₁ -C₄.

This invention also relates to the use of the enantiomeric ureas andthioureas derived from the resolved cycloalkano[b]thiophen-4-amines forenhancing the growth rate of animals and for improving feed efficiencyin the rearing of said animals.

Heretofore, a number of animal growth-promoting agents such as thetetracycline-type antibiotics, penicillin and zinc bacitracin, andhormonal agents such as diethylstilbestrol, have been used successfullyto improve feed efficiency and increase the growth rate of poultry andfarm animals. However, with the increasing demand for greater foodproduction, skyrocketing animal feed costs and a withdrawal of certaingrowth-promoting agents from the market place, it is now imperative thatnew methods and compositions be provided which will enhance the growthrate of animals and improve feed conversion (i.e., the ratio of unitweight of feed consumed per unit weight of gain) in the raising of saidanimals.

Surprisingly, we have discovered that in veterinary homothermic animalsfeed efficiency in the raising of poultry, such as chickens and turkeys,fur-bearing animals (i.e., animals raised for their pelts), and farmanimals (i.e., livestock such as sheep, cattle, swine and goats) can beimproved by orally or parenterally administering to the host animal aneffective amount of a cycloalkano [b]thien-4-ylurea or thiourea or thephysiologically active optical isomer thereof. We have also found thatthe administration of said compounds measurably enhances the growth rateof said animals.

In accordance with this invention, the growth rate of veterinaryhomothermic animals as poultry, fur-bearing and farm animals ismeasurably improved when a formula (I) cycloalkano[b]thien-4-ylurea orthiourea or its optically active isomer thereof is administered to theabove-said host animal in, or with, the feed in an amount equivalent tobetween 0.0001% and 0.08%, and preferably 0.001% to 0.04% by weight ofthe feed.

In practice, the active material will generally be formulated as apremix and/or an animal feed supplement which is admixed with anutritionally balanced feed or added to said feed as top dressing, orthe like. Premixes may be prepared by blending about 70% to 99% byweight of rice flour, ground rice hulls, ground corn, or the like, withabout 1% to 30% by weight of a formula (I) cycloalkano[b]thien-4-yl-ureaor thiourea compound or an optically active isomer thereof.

The growth rate of animals is also improved when a formula (I)cycloalkano[b]thien-4-ylurea or thiourea is administered as asubcutaneous implant under the skin of the animal. Implants aregenerally in the form of a paste or pellet which permits the activecompound to be released into the bloodstream of the animal over anextended period of time; as for example, from several weeks to severalmonths.

Whether the implant is in the form of a paste or a pellet is a matter ofchoice. Pellet-type implants which can be used in accordance with thisinvention may be prepared by admixing from about 50% to 95% by weight ofa compound of formula (I) with from about 50% to 5% by weight of apharmaceutically acceptable carrier such as Castorwax (i.e., glyceryl12-hydroxystearate), white wax, beeswax, starch, or a high molecularweight (i.e., 4000) polyethylene glycol, or mixtures thereof, alone orin combination with a small amount of a lubricant such as zinc stearateor magnesium stearate. A small amount of polyvinylpyrrolidone anddibutylphthalate may also be incorporated in the above-saidformulations.

Paste implants can be prepared using the same percentages of drug asstated above, but employing a mixture of high molecular weight (i.e.,4000) polyethylene glycol and low molecular weight (i.e., 400)polyethylene glycol alone, or in combination with, Castorwax or beeswaxand/or polyvinylpyrrolidone.

Implants may vary in size and weight, but usually range between 10 mg.and 100 mg. per implant. Advantageously, with this method ofapplication, the drug can be administered at periodic intervalsthroughout the feeding period of the animals. Moreover, formulations andintervals between implantations can be varied to provide a daily drugrelease of generally about 0.0005 mg. to 0.2 mg. per kg. of body weight,and preferably 0.001 mg. to 0.1 mg. per kg. of body weight.

Typical animal feed supplements and implant formulations are as follows:

    __________________________________________________________________________    Beef Cattle Supplement                                                                          Feed Rate                                                                     2 lbs/Head/Day                                                                          1 lb/Head/Day                                     __________________________________________________________________________    Dehydrated Alfalfa Meal (17%)                                                                   13.0%     26.5%                                             Cotton Seed Meal (41%)                                                                          13.5%     27.0%                                             Limestone (33%)   11.0%     22.0%                                             Urea (2.81%)      6.0%      12.0%                                             Dried Molasses    2.5%      5.0%                                              Salt, Iodized     2.5%      5.0%                                              Vitamin-Mineral Premix (1)                                                                      1.0%      2.0%                                              Drug Premix (2)   0.5%      0.5%                                              Ground Corn       50.0%     --                                                __________________________________________________________________________    (1) Vitamin-Mineral Premix (per 1000 lbs. of supplement)                      Vitamin A (30,000 I.U./g.)                                                                        833 g.   1666 g.                                          Cobalt Sulfate (CoSO.sub.4 · 7H.sub.2 O)                                                 2 g.     4 g.                                             Copper Sulfate (CuSO.sub.4 · 5H.sub.2 O)                                                 78 g.    156 g.                                           Manganese Oxide (Mno)                                                                             32 g.    64 g.                                            Zinc Oxide (ZnO)    62 g.    124 g.                                           Elemental Sulfur    2000 g.  4000 g.                                          Dehydrated Alfalfa Meal                                                                           1533 g.  3066 g.                                                              4540 g.  9080 g.                                          __________________________________________________________________________    (2) Drug Premix (per 1000 lbs. of supplement)                                 Formula (I)                                                                   Cycloalkano[b]thien-                                                                      Amount        Amount in Premix                                    4-ylurea or thio-                                                                         in Premix     1 lb. of Supplement/                                urea        2 lb. of Supplement/Day                                                                     Day                                                 Level of Drug per                                                             Head/Day    Drug Ground Corn                                                                            Drug                                                                              Ground Corn                                     (mg.)       (g.) (g.)     (g.)                                                                              (g.)                                            __________________________________________________________________________    400         200  2070     400 1870                                            200         100  2170     200 2070                                            100          50  2220     100 2170                                             50          25  2245      50 2220                                             0           0   2270      0  2270                                            __________________________________________________________________________    Typical Pellet Implant Formulations                                                                         Preferred                                       __________________________________________________________________________    (A)                                                                              4,5,6,7-Tetrahydrobenzo[b]thien-4-ylurea                                                                 50.0%*                                             (50% to 95%)                                                                  Lubricant (i.e., magnesium stearate)                                                                     0.5%*                                              Glyceryl 12-Hydroxystearate - QS                                           (B)                                                                              1-Methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-                                                             60.0%                                              4-yl)urea                                                                     Polyethylene glycol 4000   10.0*                                              Beeswax - QS                                                               (C)                                                                              1-Methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-                                                            30.0 mg                                            4-yl)urea                                                                     Beeswax                    1.0 mg.                                            Magnesium stearate         1.5 mg.                                            Dibutylphthalate           1.0 mg.                                            Polyvinylpyrrolidone (10% Solution) - QS                                   __________________________________________________________________________    Typical Paste Implant Formulation                                                                           Preferred                                       __________________________________________________________________________    (A)                                                                              1-Hydroxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo-                                                           200 mg.                                            [b]thien-4-yl)urea (100 mg. to 600 mg.)                                       Polyethylene glycol 4000 (30% to 50%)                                                                    40%*                                               Polyethylene glycol 400 - QS                                               __________________________________________________________________________     *Percent by weight.                                                      

Some of the active compounds of the present invention (VI) may bereadily prepared by reacting an appropriately substitutedcycloalkano[b]thiophen-4-amine (VII) with an appropriately substitutedisocyanate or isothiocyanate (VIII) as set forth in the followingreaction scheme: ##STR29## wherein X, Y, n, R₁, R₂, R₄, R₅ and R₆ are ashereinabove defined. The reaction can be carried out using approximatelyequimolar amounts of the isocyanate or isothiocyanate and the amine oramine acid salt; however, it is generally preferable to employ from 5%to 50% excess of the isocyanate or isothiocyanate wherein thecycloalkano ring does not contain a hydroxyl group. The reaction can beconducted at atmospheric or superatmospheric pressure at a temperaturein the range of 0° C. to 100° C., but is preferably conducted atatmospheric pressure at 0° C. to 70° C. in the presence of an organicsolvent. Suitable organic solvents include aprotic aromatic solventssuch as benzene, toluene, and xylene; chlorinated hydrocarbon solventssuch as methylene chloride, chloroform, and dichloroethane; ethers suchas tetrahydrofuran, diethyl ether, dimethoxyethane, diethylene glycoldimethyl ether, and dioxane; lower alkyl C₁ -C₄ ketones such as actone,methyl ethyl ketone, methyl butyl ketone, and methyl isobutyl ketone, ormixtures of said solvents.

When the above reaction is carried out using acycloalkano[b]thiophen-4-amine acid salt, it is desirable to add an acidacceptor to the reaction mixture. Suitable acid acceptors includetrialkylamines such as triethylamine, trimethylamine, pyridine or thelike; alkali metal carbonates such as sodium and potassium carbonate;alkaline earth metal carbonates such as calcium carbonate; strong basicion exchange resins; and aqueous alkali in a 2-phase system using animmiscible hydrocarbon solvent such as benzene or toluene, or achlorinated hydrocarbon such as chloroform or dichloroethane.

Formula (I) cycloalkano[b]thien-4-ylurea or thieourea compounds whereinR₂ and R₃ are hydrogen may be advantageously prepared from theabove-identified amine (VII) or its acid salt by reacting said aminewith an approximately equimolar amount of sodium or potassium cyanate orthiocyanate. However, it is generally preferable to employ 5% to 50%excess of the cyanate or thiocyanate wherein the cycloalkano ring doesnot contain a hydroxy group. The reaction can be conducted under theconditions described above in detail. Suitable solvents include water,polar solvents such as C₁ -C₃ alcohols, tetrahydrofuran, dioxane,ethylene glycol dimethyl ester, diethylene glycol, dimethyl ether,acetone, methyl ethyl ketone and the like and mixtures thereof; in thepH range of 5 to 7 and preferably at pH 6.

Certain of the formula (I) cycloalkano[b]thien-4-ylurea or thioureacompounds (XI) may be readily prepared by reacting approximatelyequimolar of an appropriately substituted cycloalkano[b]thien-4-ylisocyanate or isothiocyanate (IX) and an appropriately substituted R₂ R₃NH amine (X) or its acid-addition salt. The reaction can be graphicallyillustrated as follows: ##STR30## wherein X, Y, n, R₂, R₃, R₄, R₅ and R₆are as hereinabove defined; with the proviso that Y is not --CHOH. Inpractice, the reaction is usually conducted with a slight excess (i.e.up to 20% excess) of the amine in the presence of a solvent, such asdescribed above. Although the reaction may be conducted atsuperatmospheric pressure and temperatures as high as 100° C., it isgenerally preferable to conduct the reaction at atmospheric pressure ata temperature between 0° C. and 80° C. When a R₂ R₃ NH amine acid saltis used it is most beneficial to introduce into the reaction mixture anacid acceptor such as described above. When an aqueous or a C₁ -C₃alcoholic ammonia or amine solution is used to the above reactionsequence, then the formula (XI) compounds are obtained wherein R₂ and R₃are as defined above.

Preparation of the isocyanates (IX) utilized in the above reaction isreadily accomplished by reacting the appropriatecycloalkano[b]thiophen-4-amines or their acid salts with phosgene,preferably under anhydrous conditions and under a blanket of inert gassuch as nitrogen. The reaction is initially carried out at a temperaturebetween about 0° C. to 40° C., preferably 10° C. to 20° C., and thenheated to between about 50° C. and 100° C., and preferably to from 60°C. to 80° C. The reaction is usually also conducted in the presence ofan organic solvent such as benzene, toluene or xylene. Theisothiocyanates (IX) can be prepared by reacting the appropriatecycloalkano[b]thiophen-4-amines with equimolar amounts of carbondisulfide, triethylamine, and a carbodiimide represented by the formula:G--N=C=N=G where G is cyclohexyl, cycloheptyl, alkyl C₄ -C₆ or the like.This reaction is generally conducted in the presence of a solvent suchas tetrahydrofuran or an ether such as diethyl ether, at a temperaturebetween about -10° C. and +25° C. The product can be isolated bydistillation or by dry-column chromatography. Alternatively, the formula(IX) isothiocyanates can be prepared by the reaction of1,1'-thiocarbonyldiimidazole with cycloalkano[b]thiophen-4-amines in thepresence of chloroform at ambient temperature.

The reaction of thiocarbonyl diimidazole in the above-mentioned reactionmay also lead to the isolation of1-(1-imidazolyl)-3-(cycloalkano[b]thien-4-yl)thiourea. The analogousreaction also occurs when carbonyl diimidazole is used at roomtemperature and these reactions may be illustrated as follows: ##STR31##where R₁, R₄, R₅, R₆, n, Y and X are previously defined. Thisintermediate (XII) has been discovered to be useful for preparing growthpromoting urea compounds especially when the corresponding 4-isocyanateor 4-isothiocyanates of the cycloalkano[b]thiophen-4-amines aredifficult to prepare by conventional methods. The reaction may beillustrated as follows: ##STR32##

The reaction is run at room temperature to 100° C. and preferably at25°-50° C. in inert solvents such as chloroform, tetrahydrofuran,methylene chloride and the like.

Advantageously, formula (I) cycloalkano[b]thien-4-ylurea or thioureacompounds wherein Y is carbonyl (XIV) may be readily prepared from thecorresponding formula (I) compounds wherein Y is methylene (XIII) by anoxidation reaction as set forth in the following reaction scheme:##STR33## wherein X, n, R₁, R₂, R₃, R₄, R₅ and R₆ are as hereinabovedefined with the proviso that R₂ cannot be hydroxyl, or a groupcontaining hydroxyl, or --SCH₃, or an aryl--CH₃, or an aryl- orheteroaryl-methylene. The oxidation is carried out by treating acompound of formula (XIII) with a 2 to 8 mole equivalent and preferablywith a 4 or 5 mole equivalent of an oxidizing agent selected from thegroup consisting of ceric ammonium nitrate, silver oxide, or sodiumbichromate, at a temperature between about 0° C. and 100° C., andpreferably 20° C. to 60° C., in a solvent selected from the groupconsisting of aqueous solutions of acetic acid, acetonitrile,tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether, which may contain nitric acid, phosphoric acid or perchloricacid; or the oxidizing agent chromic anhydride in acetic anhydridefollowed by hydrolysis.

Furthermore, formula (I) cycloalkano[b]thien-4-yl-urea or thioureacompounds wherein Y is carbonyl (XVIII) can also be prepared by theabove-described oxidative process as set forth in the following reactionscheme: ##STR34## wherein Z is methylene or hydroxymethylene and X, n,R₂, R₃, R₄, R₅ and R₆ are as hereinabove defined. Upon completion of theoxidation step, the resulting 7-oxo compounds (XVI) are hydrolyzed indilute mineral acid. The thus-obtained amine (XVII) acid-addition saltsare then reacted with an isocyanate or an isothiocyanate at pH 5-7 ashereinbefore described in detail to yield the desired ureas or thioureas(XVIII).

The corresponding 7-hydroxy analogs are prepared from the correspondingformula (I) compounds wherein Y can be only carbonyl by reduction withequimolar or excess amounts of sodium borohydride, at a temperaturerange between about 0° C. and 75° C., preferably 20°-40° C., in C₁ -C₃alcohols to afford a mixture of the cis and trans isomers. All of thehereinabove-described processes for the preparation of formula (I)cycloalkano[b]thien-4-ylurea compounds yield racemic (dl) mixtures.

The active compounds of the present invention may also be readilyprepared by treating an appropriately substitutedcycloalkano[b]thiophen-4-amine (VII) with an appropriately substitutedcarbamoyl or thiocarbamoyl halide (XIX) as set forth in the followingreaction scheme: ##STR35## wherein R₁, R₂, R₃, R₄, R₅, R₆, n, X and Yare as hereinabove defined and halide may be chloro or bromo with theproviso that R₂ may not be hydroxyl, or a group containing hydroxyl, ora thioether. The free base of (VII) may be employed or an acid-additionsalt thereof, preferably the hydrochloride, in the presence of an acidacceptor. Suitable acid acceptors may be pyridine, triethylamine (or anysuitable tertiary amine), alkali metal carbonates such as potassiumcarbonate and sodium carbonate, strong basic ion-exchange resins, andaqueous alkali. The reaction may be run from about room temperature upto about 100° C. and preferably at 25°-50° C. until the desired reactionis complete. The reaction may be carried out under aqueous conditions orin any inert organic solvent such as tetrahydrofuran, dimethoxyethane,and even alcohols. The carbamoyl chloride or thiocarbamoyl chloride isgenerally used in equivalent amounts but it may be used in excess.

The preparation of the optically active cycloalkano[b]thiophen-4-aminewhich is a useful intermediate for the synthesis of optically activecycloalkano[b]thien-4-ylureas or thioureas of formula (I) may beaccomplished as follows. The racemic (dl) cycloalkano[b]thiophen-4-amineis treated with the (+)-N-benzoylglutamic acid to form a water-insolublesalt of (+)-cycloalkano[b]thiophen-4-amine in high yield. It is notnecessary to employ more than one mole of the resolving acid for eachtwo moles of dl amine, as a cheaper acid, preferably acetic acid, can besubstituted for the balance of required acid. In this way it is possibleto obtain a high yield of the desired (+)-amine based on the resolvingacid. The resolved salt, (+)-cycloalkano[b]thiophen-4-amine.(+)-N-benzoylglutamic acid, is treated with alkali which liberates the(+)-amine which separates as an insoluble phase. It can be mechanicallyseparated from the aqueous phase or extracted conventionally with asuitable solvent.

The (-)-amine which remains in solution is then recovered and treatedwith (-)-N-benzoylglutamic acid and acetic acid in the above-mentionedmanner with the molarity adjusted to the amount of (+) amine obtainedfrom the initial resolution. The salt,(-)-cycloalkano[b]thiophen-4-amine (-)-N-benzoylglutamic acid,crystallizes and is then treated in the above-mentioned manner to givethe (-)-amine.

With respect to optical isomers, the most preferred optically activeureido and thioureido compounds for enhancement of growth in animals arethose which are derived from the (+)-cycloalkano[b]thiophen-4-amine.Thus, the following reaction schemes will exemplify the sequence in thepreparation of the optically active compounds. ##STR36##

The separation of the cis- andtrans-(-)-7-hydroxy-cycloalkano[b]thien-4-ylureas and thioureas isreadily achieved by using preparative high-pressure liquidchromatography on silica gel with 1800 ml. of hexane/1000 ml. of CHCl₃/425 ml. of MeOH at a flowrate of 40 ml./minute. Since theconfigurations have not been established, the isomers are designated asIsomer A and Isomer B. Conversely, if (-)-cycloalkano[b]thiophen-4-amineis used in the above sequence, the resulting derivatives of the oppositesign are obtained.

Because 7-oxo-cycloalkano[b]thiophen-4-amine is also a usefulintermediate, this compound in its optically active form is desirable.Thus, dl-7-oxo-cycloalkano[b]thiophen-4-amine is readily resolved with(+)-tartaric acid in methanol as follows: ##STR37## and the resultingcrystalline tartrate salt is recrystallized from 95% ethanol. The saltis decomposed with aqueous NaOH solution and the optically activeketo-amine is separated by conventional extraction and acidified withHCl to afford (-)-7-oxo-cycloalkano[b]thiophen-4-amine hydrochloride,which can be used in the manner described above.

The present invention is further illustrated by the preparation ofrepresentative examples set forth below, as well as testing data ontypical compounds of the invention.

EXAMPLE 1 Preparation of1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

A mixture of 1.89 grams (0.01 mole) of4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. ofdry benzene is stirred while 1.05 grams (0.01 mole) of triethylamine and01.7 ml. (excess) of methyl isocyanate are added successively. Additionof the latter gives rise to an exotherm, and the mixture becomes verypasty. The mixture is kept at 45° C. for 1 hour, and after cooling toroom temperature, the solid is collected, washed thoroughly with benzeneand then with water. On drying, this gives 1.7 grams (81%) of product,melting point 183° C. to 186° C. Recrystallization from acetone gives1.23 grams, melting point 187.5° C. to 189° C.

On a 0.05 mole scale, the crude yield is 83% (9.15 grams), and theproduct melts at 181° C. to 186° C. Recrystallization from acetone gives6.5 grams, melting point 184.5° C. to 187° C.

EXAMPLE 2 Preparation of1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

In the manner described in Example 1, ethyl isocyanate is allowed toreact with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride toafford 10.1 grams of1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Recrystallizationof the crude product from 2-propanol-water (9/1) affords crystals whichare dissolved in chloroform and washed successively with 1N sulfuricacid, water and saturated sodium bicarbonate solution. This gives thedesired product, melting point 184° C. to 188.5° C. after evaporation ofthe chloroform.

EXAMPLE 3 Preparation of1-isopropyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

In a nitrogen atmosphere, 5.35 grams of4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is stirred in 100 ml. ofdiethyl ether, and 3.57 grams of isopropyl isocyanate in 40 ml. ofdiethyl ether is slowly added to afford crystalline product. The mixtureis stirred for an additional 0.5 hour and then filtered after standingovernight to give 8.3 grams, melting point 223° C. to 226° C., of1-isopropyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

EXAMPLE 4 Preparation of1-(n-hexyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

In the manner described in Example 1,4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is allowed to react withn-hexyl isocyanate to give1-(n-hexyl)-3-(4,5,6,7-tetrahydrobenzo[b]-thien-4-yl)urea, melting point122° C. to 124° C.

EXAMPLE 5 Preparation of1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4yl)urea

In a similar manner, as described in Example 1,4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is allowed toreact with cyclohexyl isocyanate in dry tetrahydrofuran to afford 7grams of 1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,melting point 222° C. to 225° C.

EXAMPLE 6 Preparation of1-methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

A mixture of 5 grams of methoxyamine hydrochloride in 60 ml. ofmethylene chloride is cooled to about 15° C., and 6 grams oftriethylamine in 15 ml. of methylene chloride is added. After 20minutes, 5.38 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanatein 20 ml. of methylene chloride is added over 20 minutes at 15° C. to20° C. After stirring for an hour, the mixture is filtered, and thefiltrate is washed with water and then aqueous sodium bicarbonatesolution. The solution is dried and evaporated to afford a white solid.The solid is recrystallized from acetone-hexane to afford 5.1 grams,melting point 138.5° C. to 141° C., of1-methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

Similarly, 1-ethoxy-3-(4,5,6,7-tetrahydrobenzo[b]-thien-4-yl)urea and1-butoxy-3-(4,5,6,7-tetrahydrobenzo[b]-thien-4-yl)urea are prepared byusing ethoxyamine hydrochloride and n-butoxyamine hydrochloride,respectively, in place of methoxyamine hydrochloride.

EXAMPLE 7 Preparation of1-benzyloxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

In the manner described in Example 6, O-benzyl hydroxyaminehydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate areallowed to react to afford1-(benzyloxy)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which isrecrystallized from 95% ethyl alcohol-methyl isobutyl ketone. Theproduct melts at 96.5° C. to 99° C.

EXAMPLE 8 Preparation of1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo-[b]thien-4-yl)urea

In the manner described in Example 6, N-methylhydroxylaminehydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate areallowed to react to afford1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, whichis recrystallized from acetone-hexane-ether to give crystals, withmelting point 98° C. to 102° C.

EXAMPLE 9 Preparation of1-methoxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo-[b]thien-4-yl)urea

Following the procedure described in Example 6, N,O-dimethylhydroxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate are allowed to react to give1-methoxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, whichis crystallized from acetone-hexane-ether to give product melting at 60°C. to 62.5° C.

EXAMPLE 10 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

A mixture of 50 grams of 4,5,6,7-tetrahydrobenzo-[b]thiophen-4-aminehydrochloride (about 45 grams real, based on 90% purity) in 100 ml. ofwater is stirred at about 15° C., and a solution of 23.1 grams ofpotassium cyanate in 100 ml. of water is added dropwise. Aftercompletion of the addition, the mixture is warmed slowly to 70° C. to75° C. and held for an hour. The mixture is cooled, and the white solidis collected by filtration and washed with water. The solid isair-dried, pulverized, and washed with acetonitrile. On drying, thisgives 37.3 grams of crude product, which on treatment with about 1200ml. of hot acetone gives 11.45 grams, melting point 200° C. to 204° C.of the title compound.

Similarly, 2-methyl- and3-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea are prepared to giveproducts melting at 232°-233° C. and 227°-230° C. (dec.), respectively.When N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochlorideis used, 1-methyl-1-(4,5,6,7-tetrahydrobenzo[b]-thien-4-yl)urea, meltingpoint 151.5°-154.5° C., is obtained.

EXAMPLE 11 Preparation of1-phenethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

A mixture of 3.82 grams of phenethylamine in 100 ml. of diethyl etherunder nitrogen atmosphere is allowed to react with 5.38 grams of4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate in 25 ml. of diethylether via dropwise addition of the latter solution. After stirring anhour at room temperature, the mixture is filtered and washed with etherto give 7.9 grams, melting point 163° C. to 166° C., of1-phenethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

In a similar manner, methylamine, ethylamine, isopropylamine,n-hexylamine and cyclohexylamine are allowed to react with theaforementioned isocyanate to afford 1-methyl-, 1-ethyl-, 1-isopropyl-,n-hexyl- and 1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.

EXAMPLE 12 Preparation of1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

A solution of 6.27 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate in 200 ml. of diethyl ether is charged with gaseousdimethylamine introduced via a capillary tube with stirring. After 0.5hour of bubbling, the gas flow is terminated, and the mixture isevaporated to dryness to give a solid residue. This is crystallized fromacetone-hexane-ether to give1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea melting at117° C. to 120° C.

The identical product is obtained when4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is allowed to react withequivalent amounts (or excess) of dimethylcarbamoyl chloride andtriethylamine in dimethylformamide. The reaction mixture is stirred forseveral hours and then filtered. The filtrate is evaporated to drynessand the residue is purified by crystallization from acetone-hexane toafford the title compound.

EXAMPLE 13 Preparation of1-benzyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

In the manner described in Example 6, except for the use of diethylether instead of methylene chloride,1-benzyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea is obtained byallowing benzylamine and 4,5,6,7-tetrahydrobenzo-[b]thien-4-ylisocyanate to react. The product melts at 211° C. to 214° C.

The title compound is also obtained by allowing benzyl isocyanate toreact with 4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine in ether.

EXAMPLE 14 Preparation of1-hydroxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

The above compound is prepared in the manner described in Example 6, byallowing 4,5,6,7-tetrahydrobenzo-[b]thien-4-yl isocyanate to react withhydroxylamine hydrochloride in the presence of triethylamine. Theproduct melts at 158.5° C. to 160.5° C.

EXAMPLE 15 Preparation ofN-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-4-morpholinecarboxamide

In the manner outlined in Example 6, except for using diethyl etherinstead of methylene chloride, 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate is allowed to react with morpholine to giveN-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-4-morpholinecarboxamide, whichmelts at 152° C. to 154° C.

EXAMPLE 16 Preparation of2-bromo-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

A sample of 7.84 grams of 4,5,6,7-tetrahydrobenzo-[b]thien-4-ylurea isdissolved in 72 ml. of acetic acid, and 24 ml. of water is added.Bromine (2.3 ml. or 7.05 grams) in 32 ml. of acetic acid is addeddropwise. The mixture is stirred at room temperature for 0.5 hour, andthen 7.23 grams of sodium acetate in 40 ml. of water is added. Anadditional 120 ml. of water is added and stirring is continued for 0.5hour. The white solid is collected, washed with water and cold sodiumacetate solution to give 9.8 grams, melting point 206.5° C. to 209.5°C., of 2-bromo-4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea.

EXAMPLE 17 Preparation of2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine

A sample of 54.3 grams ofN-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is stirred in 270ml. of acetic acid and 90 ml. of water. Bromine (53 grams) in 120 ml. ofacetic acid is added gradually. After stirring for 0.5 hour at roomtemperature, 61.5 grams of sodium acetate in 225 ml. water is added.More water is added, and the mixture is extracted with ether. Methylenechloride is added to the ether solution to prevent crystallization, andthe solution is evaporated to dryness. The residue is crystallized fromacetone-hexane-ether to afford 61 grams, melting point 104° C. to 108°C., of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine.

EXAMPLE 18 Preparation of2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine

A mixture of 40.9 grams of2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, 16.2 gramsof cuprous cyanide and 47 ml. of dry dimethylformamide is heated atreflux temperature for 4 hours, and then cooled to about 60° C. andpoured into 270 ml. of water. The mixture is extracted with tolueneseveral times, and the toluene extracts are washed with 1.2Nhydrochloric acid and saturated sodium chloride respectively. On drying,5.7 grams of crude product is obtained. The aqueous mother liquor istreated with 97.3 grams of ferric chloride hexahydrate and 30 ml. ofconcentrated hydrochloric acid and shaken. It is then extracted withtoluene several times, and the extracts are washed further with 1.2Nhydrochloric acid, saturated sodium bicarbonate solution and brine,respectively. On drying and evaporation of toluene, an additional 2.5grams of product is obtained. The two crops are combined andrecrystallized from acetone-hexane to afford 4.8 grams of2-cyano-N-formyl-4,5,-6,7-tetrahydrobenzo[b]thiophen-4-amine, meltingpoint 131° C. to 134° C.

EXAMPLE 19 Preparation of2-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride

A mixture of 4.8 grams of2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 70 ml. of1N hydrochloric acid is refluxed for an hour and evaporated to drynessto afford 4.7 grams of2-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride,melting point 241° C. to 246° C. (dec.).

EXAMPLE 20 Preparation of2-cyano-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

The desired product, 2-cyano-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea,is prepared in the manner described in Example 10 by allowing2-cyano-4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine hydrochloride toreact with potassium cyanate. The crude product melts at 210° C. to 214°C., and the product which is recrystallized from nitromethane melts at209° C. to 213° C.

EXAMPLE 21 Preparation of2-chloro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine

A sample of 11.4 grams 4,5,6,7-tetrahydrobenzo[b]-thiophen-4-aminehydrochloride is stirred in 150 ml. of chloroform at about 10° C., and6.1 ml. of sulfuryl chloride is added dropwise. The mixture is stirredfor 3.5 hours at room temperature, and then about 20 ml. of 50% sodiumhydroxide solution is added gradually to dissolve the suspended solid.The mixture is then poured into water and extracted with chloroformtwice. The extracts are dried, evaporated to dryness, and the residue isdistilled to give 7.4 grams of2-chloro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, boiling point 94°C. to 98° C./0.5 Torr.

EXAMPLE 22 Preparation of2-chloro-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

The desired product, 2-chloro-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea,is prepared in the manner described in Example 31 by allowing2-chloro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine to react withhydrocyanic acid in situ. The product melts at 194° C. to 198° C.

EXAMPLE 23 Preparation ofN-(2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide

N-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (19.5 grams) isstirred in 300 ml. of methylene chloride in a nitrogen atmosphere, and17 ml. of acetyl chloride is added. The mixture is cooled to about 10°C., and 28.1 ml. of stannic chloride is added slowly. After stirring for1.5 hours at room temperature, the mixture is cooled to about 10° C.,and 450 ml. of 1.2N hydrochloric acid is added. The mixture is shaken,and the methylene chloride solution is separated and washed with 1Nhydrochloric acid, followed by saturated sodium bicarbonate solution. Ondrying and evaporating to dryness, crystals are obtained.Recrystallization from acetone-hexane gives 15.4 grams, melting point167.5° C. to 172° C., ofN-(2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide.

EXAMPLE 24 Preparation of2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride

The product from Example 23 (7.25 grams) is heated with 90 ml. of 1Nhydrochloric acid at reflux temperature for 8.5 hours and cooled. Themixture is diluted with water and extracted with methylene chloride. Theaqueous layer is then evaporated to dryness using 2-propanol forfacilitating removal of water. This gives 4.85 grams of2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride.

EXAMPLE 25 Preparation of2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

A sample of 6.3 grams of2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride isdissolved in 35 ml. of water and cooled to 15° C. A solution of 2.64grams of potassium cyanate in 35 ml. of water is added, and after 0.5hour the mixture is heated at 70° C. for about 40 minutes. The mixtureis cooled, and the solid is collected and washed with water. On drying,5.55 grams, melting point 218° C. to 220° C., of2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is obtained.

EXAMPLE 26 Preparation of1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea

A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride is stirred in 100 ml. of dry tetrahydrofuran, and 6.06grams of triethylamine is added. After stirring for 15 to 30 minutes,5.23 grams of ethyl isothiocyanate in 20 ml. of dry tetrahydrofuran isadded dropwise, and the mixture is heated for 2 hours at 50° C. Themixture is cooled and filtered, and the filter cake is washed withhexane. The filtrate is evaporated to dryness and poured on ice. The oilis extracted with ether, and the extract is washed with 1N sulfuricacid, water, and saturated sodium bicarbonate solution. The etherextract is dried and evaporated to dryness to afford an oil. This oilcrystallizes in ether to afford1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea, melting point106° C. to 112° C.

Similarly, use of methyl isothiocyanate, butyl isothiocyanate andcyclohexyl isothiocyanate affords 1-methyl-, 1-butyl- and1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thioureas.

EXAMPLE 27 Preparation of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine

A sample (61.2 grams) of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride is suspended in 150 ml. of water, and about 400 ml. of 10%aqueous ammonium hydroxide is added to the mixture. The alkaline mixtureis then extracted twice with ether, and after drying the etherealsolution is evaporated to dryness. The amine is then distilled to give40.9 grams, boiling point 100° C. to 102° C. at 3 Torr., of4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine.

EXAMPLE 28 Preparation of(-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ammonium (R)-N-benzoylglutamate

A mixture of 8.04 grams of (R)-(+)-N-benzoyl glutamic acid in 1.92 gramsof acetic acid and 80 ml. of water is heated on a steam bath until asolution is obtained. This hot solution is stirred while 9.80 grams of4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added gradually. About 2ml. of ethanol is used in the transfer as a rinse for the amine. Themixture is then allowed to cool to room temperature and to standovernight. The mixture is cooled in a refrigerator, filtered to collectthe crystals, and the filter cake is washed with water several times. Ondrying, this gives 9.27 grams of the title salt, melting point 192° C.to 194° C.; [α]₅₈₉ ²⁵ -9.39° , [α]₄₃₆ -44.6° , [α]₃₆₅ -71.4° at c =4.475 in acetic acid.

The original filtrate is concentrated under reduced pressure to a smallvolume and partitioned between diethyl ether and aqueous sodiumhydroxide. The aqueous base is extracted with ether, and this etherextract is combined with the first ether fraction. This is then driedover magnesium sulfate, evaporated to dryness to afford the recoveredamine, and the amine is added to a stirred, hot solution of 8.04 gramsof (S)-(-)-N-benzoyl glutamic acid in 1.92 grams of acetic acid and 80ml. of water. Crystallization occurs rapidly, and after 10 minutes ofheating on a steam bath, the mixture is allowed to cool in arefrigerator. The crystals are collected, washed with water and dried toafford 11.1 grams of (+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ammonium(S)-N-benzoyl glutamate salt, melting point 192° C. to 193.5° C.,[α]₅₈₉.sup. 25 +12.2° , [α]₄₃₆ + 42.7° , [α]₃₆₅ + 82° at c = 4.35 inacetic acid.

EXAMPLE 29 Preparation of (-) 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

The salt (8.8 grams of (-)-4,5,6,7-tetrahydrobenzo-[b]thiophen-4-amineand (R)-(+)-N-benzoyl glutamic acid is added to ice water mixture in aseparatory funnel, and 3.5 grams of sodium hydroxide in 55 ml. of wateris added. The mixture is shaken until a solution is obtained, and thenis extracted with diethyl ether twice. The ether extracts are washedwith saturated sodium chloride solution, and with ice added the mixtureis extracted with 2.36 ml. of concentrated hydrochloric acid in 25 ml.of water. The acid layer is then treated with 2.29 grams of potassiumcyanate in 30 ml. of water at 20° C. After stirring for an hour, themixture is heated to 0.5 hour and cooled. The product is collected byfiltration, washed with water, and dried to give 2.75 grams, meltingpoint 218.5° C. to 221.5° C.; [α]₅₈₉.sup. 25 - 63.2° , [α]₄₃₆ -149.9° ,[α]₃₆₅ -271.5° , of (-)-4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea.

Similarly, the salt of (+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amineand (S)-(-)-N-benzoyl glutamic acid is treated in the above manner toafford (+)-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point 218°C. to 220° C.; [α]₅₈₉.sup. 25 +60° , [α]₄₃₆ +149.8° , [α]₃₆₅ +272.5°.

EXAMPLE 30 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4 -ylisocyanate

A sample of 47.6 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride is stirred in 150 ml. of water, and 350 ml. of 10% sodiumhydroxide is added. The mixture is shaken and extracted with benzenetwice. The extract is dried and evaporated to dryness to afford theamine, which is stored under nitrogen. The amine is then added dropwiseto 866 ml. of 12.5% phosgene solution (benzene) in nitrogen atmosphereat 20° C. After stirring for an hour at room temperature, the mixture isgradually heated to 60° C. and kept at this temperature for 7 hours. Themixture is cooled to room temperature and evaporated to dryness toafford a residue, which is distilled to give 22.4 grams, boiling point98° C. to 101° C./0.6 Torr., of 4,5,6,7-tetrahydrobenzo[b]thien-4ylisocyanate.

EXAMPLE 31 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

A sample of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (19.9 grams) iscooled in a flask, and a solution of 12 ml. of 12N hydrochloric acid in50 ml. of water is slowly added. Subsequently, at about 20° C., asolution of 11.7 grams of potassium cyanate in 80 ml. of water is addedin 0.5 hour. The mixture is stirred at room temperature for one hour andthen warmed to 60° C. and kept at this temperature for 0.5 hour. Afterstanding overnight at room temperature, the product is collected andwashed with water to afford 21 grams, melting point 206° C. to 209° C.

EXAMPLE 32 Mouse Growth Regulant Tests

CFI female mice from Carworth Farms are received when they are six weeksold. They are housed ten to a cage in air-conditioned rooms (72° F. to76° F.) with automatically controlled lights, 14 hours on and 10 hoursoff. The basal diet used in these studies is Purina Laboratory Chow (seedescription below), which is supplied ad libitum. Water is also allowedad libitum.

Thirteen days after arrival, the mice are weighed in groups of ten andassigned at random to the different treatments. The concentration of thedifferent compounds in the diet is indicated in the following tables.Twelve days later the mice are weighed again and the experimentterminated. At least three cages (30 mice) of untreated controls areincluded in each test. Test data are provided in Tables VI, VII, VIII,and IX below wherein data are reported as percent weight gain overcontrols. Unless otherwise indicated in these tables, all compoundstested were dl-racemic mixtures. The following is a description of thediet to which the growth promoting compounds were added.

    ______________________________________                                        DIET                                                                          GUARANTEED ANALYSIS                                                           Crude protein not less than                                                                          23.0 %                                                 Crude fat not less than                                                                              4.5 %                                                  Crude fiber not more than                                                                            6.0 %                                                  Ash not more than      9.0 %                                                  INGREDIENTS                                                                   Meat and bone meal, dried skimmed milk, wheat                                 germ meal, fish meal, animal liver meal, dried                                beet pulp, ground extruded corn, ground oat                                   groats, soybean meal, dehydrated alfalfa meal,                                cane molasses, animal fat preserved with BHA,                                 vitamin B.sub.12 supplement, calcium pantothenate,                            choline chloride, folic acid, riboflavin sup-                                 plement, brewers' dried yeast, thiamin, niacin,                               vitamin A supplement, D activated plant sterol,                               vitamin E supplement, calcium carbonate, di-                                  calcium phosphate, iodized salt, ferric ammonium                              citrate, iron oxide, manganous oxide, cobalt                                  carbonate, copper oxide, zinc oxide.                                          ______________________________________                                    

                                      TABLE VI                                    __________________________________________________________________________    Effectiveness of 4,5,6,7-Tetrahydrobenzo[b]thien-4-ylureas as                 Animal Growth Promoting Agents Reported as Percent Weight                     Gain Over Controls Using Mice as the Test Animal                               ##STR38##                                                                                                                     % Weight                     Rate ppm                                         Gain over                    in Diet                                                                            X  R.sub.5                                                                           R.sub.6                                                                           R.sub.1                                                                           R.sub.3   R.sub.2            Controls                     __________________________________________________________________________     50  O  H   H   H   H         H                  50.1                         400  O  H   H   H   H         H                  119.6                         50  O  H   H   H   H         CH.sub.3           61.8                         200  O  H   H   H   H         H                  134.2                         50  O  H   H   H   H         C.sub.2 H.sub.5    40.3                         200  O  H   H   H   H         C.sub.2 H.sub.5    87.6                         400  0  H   H   H   CH.sub.3  OH                 49.6                         400  0  H   H   H   H         OCH.sub.3          68.6                         400  0  H   H   H   CH.sub.3  CH.sub.3           55.1                         400  0  H   H   H   CH.sub.3  OCH.sub.3          106.8                        400  0  H   H   H   H         CH(CH.sub.3).sub.2 88.0                         400  0  Br  H   H   H         H                  76.3                         400  0  Cl  H   H   H         H                  4.8                          400  0  H   H   CH.sub.3      H                  27.2                         400  S  CH.sub.3                                                                          H   H   CH.sub.3  H                  88.5                         400  0  H   H   H   H         H                  122.5                                            (levorotatory                                                                 enantiomorph)                                             400  O  H   H   H   H         CH.sub.3           134                          400  O  H   H   H   H         C.sub.2 H.sub.5    87.6                         400  O  H   H   H   H         n-hexyl            14.5                         400  O  H   H   H   H         CH.sub.2 C.sub.6 H.sub.5                                                                         32.4                         400  O  H   H   H   H         CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                                72.3                         400  S  H   H   H   H         C.sub.2 H.sub.5    54.6                         400  O  H   H   H   CH.sub.2CH.sub.2OCH.sub.2CH.sub.2                                                                          9.9                          400  0  H   H   H   H         CH.sub.2CHCH.sub.2 48.4                         400  0  H   H   H   H                                                                                        ##STR39##         43                           400  0  H   H   H   CH.sub.2CH.sub.2CH.sub.2CH.sub.2                                                                           18                           400  O  H   H   H                                                             n-butyl                                                                       n-butyl                                          6                            400  S  H   H   H   H         H                  11                           400  S  H   H   H   H                                                                                        ##STR40##         15                           400  S  H   H   H   H                                                         n-butyl                                                                            75                                                                       400  O  H   H   H   H         CH.sub.2CH.sub.2OH 3                            400  S  H   H   H   H                                                         n-C.sub.8 H.sub.17                                                                 16                                                                       400  S  H   H   H   H                                                                                        ##STR41##         32                           400  S  H   H   H   H         CH.sub.2CHCH       60                           400  O  H   H   H   H         CH.sub.2CCH        82                           400  O  H   H   H   H                                                                                        ##STR42##         4                            400  O  H   H   H   H         CN                 1                            400  O  H   H   H   H                                                                                        ##STR43##         1                            400  O  H   H   H   H                                                                                        ##STR44##         8                            200  O  H   H   H   H                                                         n-butyl                                                                            25                                                                       400  O  H   H   H   H         CH.sub.2OCH.sub.3  102                          400  O  H   H   H   H         CH.sub.2 CN        12                           400  O  H   H   H                                                                                  ##STR45##                   14                           400  O  H   H   H   H                                                                                        ##STR46##         18                           400  O  H   H   H   CH.sub.3  CH.sub.2 CCH       29                           400  O  H   H   H   H         NHCO.sub. 2 CH.sub.3                                                                             18                           400  O  H   H   H   H                                                                                        ##STR47##         29                           400  O  H   H   H   H                                                                                        ##STR48##         78                           400  O  H   H   H   CH.sub.2CHCH.sub.2                                                                      CH.sub.2CHCH.sub.2 4.0                          400  O  H   H   H   H                                                                                        ##STR49##         39                           400  O  H   H   H   CH.sub.2CCH                                                                             CH.sub.2CCH        27                           400  O  H   H   H   H                                                                                        ##STR50##         48                           400  O  H   H   H   H                                                                                        ##STR51##         6                            400  O  H   H   H   H                                                                                        ##STR52##         21                           400  O  H   H   H   H                                                                                        ##STR53##         16                           400  O  H   H   H   H                                                                                        ##STR54##         41                           400  O  H   H   H   H                                                                                        ##STR55##         46                           400  O  H   H   H                                                                                  ##STR56##                   3                             400 O  H   H   H   H         CH.sub.2 CF.sub.3  19                           400  O  H   H   H   H                                                                                        ##STR57##         1                            400  O  H   H   H                                                                                            ##STR58##         4                            400  O  H   H   H   CH.sub.3  CH.sub.2 C.sub.6 H.sub.5                                                                         14                           400  O  H   H   H   H         CH.sub.2CH(OCH.sub.3).sub.2                                                                      22                           400  O  H   H   H   H                                                                                        ##STR59##         31                           400  O  H   H   H   H                                                                                        ##STR60##         11                           400  O  H   H   H   CH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.2CCH        30                           400  O  H   H   H                                                                                  ##STR61##                   24                           400  O  H   H   H                                                                                  ##STR62##                   7                            400  O  H   H   H   H                                                                                        ##STR63##         9                            400  O  H   H   H   H                                                                                        ##STR64##         4                            400  O  H   H   H   H                                                                                        ##STR65##         8                            400  O  H   H   H   H                                                                                        ##STR66##         9                            400  O  H   H   H   H         OH                 102.9                        400  O  H   H   H   H         OCH.sub.2 C.sub.6 H.sub.5                                                                        7.8                          400  S  H   H   H   CH.sub.3  OCH.sub.3          66                           400  O  H   H   H   H         OC.sub.2 H.sub.5   61                           400  O  H   H   H   H         OCH.sub.2CHCH.sub.2                                                                              5                            400  O  H   H   H                                                                                  ##STR67##                                                                              OH                 19                           400  O  H   H   H   H         On-C.sub.6 H.sub.13                                                                              29                           400  O  H   H   H   CH(CH.sub.3).sub.2                                                                      OH                 32                           400  O  H   H   H   CH.sub.2 C.sub.6 H.sub.5                                                                OH                 12                           400  O  CH.sub.3                                                                          H   H                                                             2-butyl                                                                            H  2                                                                     400  O  H   CH.sub.3                                                                          H   H         H                  26                           400  O  H   CH.sub.3                                                                          H   H                                                         n-hexyl                                                                            21                                                                       400  O  CH.sub.3                                                                          CH.sub.3                                                                          H                                                             2-butyl                                                                            H  3                                                                     400  O  CH.sub.3                                                                          CH.sub.3                                                                          H   H         H                  0                            400  O  NO.sub.2                                                                          H   H   H         H                  17                           400  O  H   H   H   H                                                                                        ##STR68##         -1.4                         400  S  H   H   H   H         CO.sub.2 C.sub.2 H.sub.5                                                                         22.3                         400  O  H   H   H   H                                                                                        ##STR69##         32.4                         400  O  H   H   H   H                                                                                        ##STR70##         25.0                         400  O  H   H   H   H         N(CH.sub.3).sub.2  3.0                          200  O  H   H   H   H                                                                                        ##STR71##         37.4                         400  S  H   H   H   H                                                                                        ##STR72##         -1.4                         400  O  H   H   H   H                                                                                        ##STR73##         90.6                         400  O  H   H   H   H         OCH.sub.2CO.sub.2 H                                                                              63.3                         400  1-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo[b]-                                                                          39                                thien-4-yl)urea                                                          400  1-methyl-3-(7,7-dimethyl-4,5,6,7-tetrahydrobenzo-                                                                         15                                [b]thien-4-yl)urea                                                       __________________________________________________________________________

                  TABLE VII                                                       ______________________________________                                        Effectiveness of 4,5,6,7-Tetrahydrobenzo[b]thien-4-ylureas                    as Animal Growth Promoting Agents Reported as Percent Weight                  Gain Over Controls Using Mice as the Test Animal                               ##STR74##                                                                    Rate ppm                           % Weight Gain                              in Diet X      R.sub.3 R.sub.2     Over Controls                              ______________________________________                                        400     O      H       CH.sub.3    64.8                                       400     O      H       CH.sub.2CHCH.sub.2                                                                        58.7                                       400     O      H       C.sub.2 H.sub.5                                                                           79.3                                       200     O      H       OCH.sub.3   71.0                                       200     O      H                                                              iso-C.sub.3 H.sub.7                                                                   84.0                                                                  200     O      CH.sub.3                                                                              CH.sub.3    58.6                                       200     O      H       CH.sub.2CCH 40.6                                       200     O      CH.sub.3                                                                              OCH.sub.3   62.6                                       200     O      CH.sub.3                                                                              OH          31.3                                        400     O      H                                                                                     ##STR75##   62.2                                      400     S      H       CH.sub.3    62.5                                       200     O      H       H           9.4                                        (dextrorotatory enantiomorph)                                                  25     O      H       H           118.6                                      (levorotatory enantiomorph)                                                   400     O      H                                                              n-C.sub.8 H.sub.17                 83.4                                       400     2-bromo-4,5,6,7-tetrahydro-7-oxo                                                                   35.9                                                     benzo[b]thien-4-ylurea                                                400     O      H                                                              n-C.sub.10 H.sub.21                15.4                                       400     O      H                                                              n-C.sub.12 H.sub.25                                                                   4.1                                                                   400     O      H                                                              n-C.sub.14 H.sub.29                                                                   9.7                                                                   400     O      H       CH.sub.2 OCH.sub.3                                                                        142.8                                      ______________________________________                                    

                                      TABLE VIII                                  __________________________________________________________________________    Effectiveness of 4,5,6,7-Tetrahydrobenzo[b]thien-4-ylureas                    as Animal Growth Promoting Agents Reported as Percent Weight                  Gain Over Controls Using Mice as the Test Animal                               ##STR76##                                                                    Rate ppm                         & Weight Gain                                in Diet                                                                             X  R.sub.3   R.sub.2       Over Controls                                __________________________________________________________________________    400   O  H         CH.sub.2CHCH.sub.2                                                                          29.1                                         200   O  H                                                                    iso-C.sub.3 H.sub.7                                                                 43.9                                                                    400   O  CH.sub.3  CH.sub.3      81.5                                         400   O  H         CH.sub.3      60.2                                          50   O  H         CH.sub.2CCH   49.2                                         200   O  CH.sub.3  OCH.sub.3     60.5                                         200   O  H         C.sub.2 H.sub.5                                                                             73.4                                         400   S  H         CH.sub.3      85.1                                         400   O  H         CH.sub.2 OCH.sub.3                                                                          123.7                                        400   O  H         OCH.sub.3     66.7                                         50    O  H         H             -11.3                                                 (dextrorotatory diastereomer,                                                 95% isomer B)                                                        25    O  H         H             74.5                                                  (levorotatory diastereomer,                                                   91.5% isomer B)                                                      25    O  H         H             54.4                                                  (levorotatory diastereomer,                                                   86% isomer A)                                                        200   O  H         H             13.5                                                  (mixture of dextrorotatory                                                    diastereomers, 62% isomer B)                                         25    O  H         H             3.7                                                   (dextrorotatory diastereomer,                                                 90% isomer A)                                                         400 400                                                                             ##STR77##                  110 99                                      __________________________________________________________________________

                  TABLE IX                                                        ______________________________________                                        Effectiveness of 5,6,7,8-Tetrahydro-4H-cyclohepta[b]thien-4-                  ylureas as Animal Growth Promoting Agents Reported as Percent                 Weight Gain Over Controls Using Mice as the Test Animal                        ##STR78##                                                                    Rate ppm                             % Weight Gain                            in Diet X      R.sub.1 R.sub.3                                                                            R.sub.2  Over Controls                            ______________________________________                                        400     O      H       H    H        54                                       400     O      H       H    CH.sub.3 41                                       400     S      H       H    C.sub.2 H.sub.5                                                                        40                                       400     O      H       H    CH.sub.2 OCH.sub.3                                                                     10                                       400     5,6,7,8-tetrahydro-8-oxo-4H-cyclo-                                                                 68.8                                                     hepta[b]thien-4-ylurea                                                ______________________________________                                    

EXAMPLE 33 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisothiocyanate

A sample (47.5 grams) of 4,5,6,7-tetrahydrobenzo[b]-thiophen-4-aminehydrochloride is stirred in methylene chloride-water and 5% sodiumhydroxide solution is added gradually until the pH is about 10. Themethylene chloride layer is removed and the aqueous layer is extractedwith methylene chloride. The organic layers are combined, dried overmagnesium sulfate, and evaporated to dryness to afford the oily amine.The amine is stirred in 500 ml. of ethyl acetate under nitrogenatmosphere and 25.4 grams of triethyamine is added. After about 15minutes, 20.9 grams of carbon disulfide is added to afford a copiusprecipitate. An additional 200 ml. of ethyl acetate is added and thesolid is pulverized with a spatula. After an hour of stirring, 51.5grams of dicyclohexyl carbodiimide is added and stirring is continuedfor an overnight period. Subsequently, the mixture is heated at about50° C. for 2 hours and cooled. The solid is removed by filtration andwashed with ethyl acetate. The filtrate is evaporated to afford amixture of solid and mostly oil. The solid is removed by filtrationafter either is added. The ether filtrate is evaporated to dryness toafford the crude isothiocyanate, which is purified by chromatography ona dry-column of silica gel using 65/35 (volume/volume) of petroleumether/methylene chloride.

EXAMPLE 34 Preparation ofN-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-4-piperidinethiocarboxamide

In 50 ml. of tetrahydrofuran, 5.85 grams of4,5,6,7-tetrahydrobenzo[b]thien-4-yl isothiocyanate is stirred and 2.81grams of piperidine is added. An exotherm is observed and a temperaturerises to about 40° C. to 50° C. After 2.5 hours, the mixture is heatedat reflux temperature for 3.5 hours. After stirring overnight, themixture is evaporated to dryness to afford a sticky yellow-brown solid.Ether is added to this material and the off-white, insoluble product iscollected. The crude product, 5.25 grams, melts at 102° C. to

EXAMPLE 35

The following compounds set forth in Table X below were prepared byusing the methods described in Example 3 and Example 5 and using thecorresponding amines (diethyl ether solvent) or amine hydrochlorides(tetrahydrofuran solvent) with the appropriate isocyanates orisothiocyanates.

                                      TABLE X                                     __________________________________________________________________________     ##STR79##                                                                                                               Reaction                                                                           Melting Point                 R.sub.5                                                                           R.sub.6                                                                           R.sub.1                                                                           X  R.sub.3   R.sub.2           Solvent                                                                            in degrees                    __________________________________________________________________________                                                    C.                            H   H   CH.sub.3                                                                          O  H         n-hexyl           ether*                                                                             70.5-74.5                     H   H   CH.sub.3                                                                          S  H         ethyl             ether                                                                              104-107                       CH.sub.3                                                                          H   H   S  H         ethyl             THF**                                                                              118-121                       CH.sub.3                                                                          H   H   O  H         ethyl             THF  209-211                       CH.sub.3                                                                          H   H   O  H         sec-butyl         THF  182.5-185                     CH.sub.3                                                                          H   H   O  H         n-hexyl           THF  118-120                       H   CH.sub.3                                                                          H   S  H         ethyl             THF  120.5-123.5                   H   CH.sub.3                                                                          H   O  H         sec-butyl         THF  197-198                       H   CH.sub.3                                                                          H   O  H         n-hexyl           THF  148-150                       H   H   H   O  H         CH.sub.2 CHCH.sub.2                                                                             THF  175-176                       H   H   H   O  H         CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                               THF  147-149                       H   H   H   S  H                                                                                        ##STR80##        ether                                                                              122-125                       H   H   H   O  H                                                                                        ##STR81##        ether                                                                              219-221                       H   H   H   O  H                                                              n-C.sub.12 H.sub.25                                                               ether                                                                             109-111                                                               H   H   H   S  H                                                                                        ##STR82##        ether                                                                              122-125                       H   H   H   O  H                                                                                        ##STR83##        ether                                                                              279-283                       H   H   H   O  (CH.sub.2).sub.4            ether                                                                              137-139                       H   H   H   O  (CH.sub.2).sub.5            ether                                                                              128-130                       H   H   H   O                                                                 n-C.sub.4 H.sub.9                                                             n-C.sub.4 H.sub.9                          ether                                                                               94-96                        H   H   H   S  H                                                                                        ##STR84##        THF  oil                           H   H   H   O  H         CH.sub.2 CH.sub.2OH                                                                             ether                                                                              140-154                       H   H   H   S  (CH.sub.2).sub.5            THF  103-106                       H   H   H   S  H                                                              n-C.sub.8 H.sub.17                         THF  66-69                         H   H   H   S  H                                                                                        ##STR85##        THF  125-129                       H   H   H   S  H         CH.sub.2 CHCH.sub.2                                                                             THF  101-103                       H   H   H   S  H                                                                                        ##STR86##        THF  123-127                       H   H   H   S  H                                                                                        ##STR87##        THF  137-144                       H   H   H   O  H         CH.sub.2CCH       ether                                                                              188-189                       H   H   H   O  H                                                                                        ##STR88##        THF  287-292                       H   H   H   O                                                                                 ##STR89##                  ether                                                                              126-128                       H   H   H   O  H                                                                                        ##STR90##        THF  175-179                       H   H   H   O  H                                                                                        ##STR91##        CH.sub.2 CL.sub.2                                                                  223-226                       H   H   H   O  CH.sub.2CHCH.sub.2                                                                      CH.sub.2 CHCH.sub.2                                                                             ether                                                                              69-72                         H   H   H   S   CH.sub.3 OCH.sub.3         CH.sub.2 CL.sub.2                                                                  74-77                         H   H   H   O  H         OC.sub.2 H.sub.5  CH.sub.2 Cl.sub.2                                                                  90-94                         H   H   H   O  H         OCH.sub.2CHCH.sub.2                                                                             CH.sub.2 Cl.sub.2                                                                  70-73                         H   H   H   O  cyclohexyl                                                                              OH                CH.sub.2 Cl.sub.2                                                                  180-181                       H   H   H   O  H         O-n-C.sub.6 H.sub.13                                                                            ether                                                                              54-57                         H   H   H   O  CH(CH.sub.3).sub.2                                                                      OH                CH.sub.2 Cl.sub.2                                                                  113-116                       H   H   H   O  CH.sub.2CHCH.sub.2                                                                      CH.sub.2CHCH.sub.2                                                                              ether                                                                              69-72                         CH.sub.3                                                                          H   H   O  H         H                 H.sub.2 O                                                                          234.5-236.5                   CH.sub.3                                                                          H   H   O  H                                                              n-C.sub.6 H.sub.13                                                                THF 111-121                                                               H   CH.sub.3                                                                          H   O  H         H                 H.sub.2 O                                                                          225-227                       CH.sub.3                                                                          CH.sub.3                                                                          H   S  H         C.sub.2 H.sub.5   THF  153-157                       CH.sub.3                                                                          CH.sub.3                                                                          H   O  H                                                              2-C.sub.4 H.sub.9                                                                 THF   181-183.5                                                           CH.sub.3                                                                          CH.sub.3                                                                          H   O  H                                                                                        ##STR92##        THF  203-209                       CH.sub.3                                                                          CH.sub.3                                                                          H   O  H         H                 H.sub.2 O                                                                          233-237                       H   H   H   O  H         CN                H.sub.2 O                                                                          142-145                       H   H   H   O                                                                                 ##STR93##                  ether                                                                              110-113                       H   H   H   O  H                                                                                        ##STR94##        ether                                                                              235-236                       H   H   H   O  H         2-adamantyl       ether                                                                              225-227                       H   H   H   O  H                                                                                        ##STR95##        ether                                                                              280-282                       H   H   H   O  H                                                              n-C.sub.4 H.sub.9                                                                 CH.sub.2 Cl.sub.2                                                                 159-161                                                               H   H   H   O  H         CH.sub.2 CN       THF  179-181                       H   H   H   O  H         CH.sub.2 CH.sub.2OCH.sub.3                                                                      ether                                                                              142-144                       H   H   H   O                                                                                 ##STR96##                  ether                                                                              139-140                       H   H   H   O  H         CH.sub.2 CH.sub.2SCH.sub.3                                                                      ether                                                                              128-130                       H   H   H   O                                                                                 ##STR97##                  ether                                                                              235-238                       H   H   H   O  H                                                                                        ##STR98##        ether                                                                              183-185                       H   H   H   O  CH.sub.3  CH.sub.2CCH       ether                                                                              105-108                       H   H   H   O  H                                                                                        ##STR99##        ether                                                                              182-185                       H   H   H   O  H         NHCO.sub.2 CH.sub.3                                                                             ether                                                                              183-186                       H   H   H   O  H                                                                                        ##STR100##       CH.sub.3 OH                                                                        278-279                       H   H   H   O  H                                                                                        ##STR101##       CH.sub.2 Cl.sub.2                                                                  171-172                       H   H   H   O  H                                                                                        ##STR102##       CH.sub.3 OH                                                                        184-187                       H   H   H   O  H                                                                                        ##STR103##       CH.sub.2 Cl.sub.2                                                                  234-237                       H   H   H   O  H                                                                                        ##STR104##       ether                                                                              195-197                       H   H   H   O  CH.sub.2CCH                                                                             CH.sub.2CCH       ether                                                                              118-120                       H   H   H   O  H                                                                                        ##STR105##       CH.sub.2 Cl.sub.2                                                                  201-204                       H   H   H   O  H                                                                                        ##STR106##       CH.sub.2 Cl.sub.2                                                                  192-195                       H   H   H   O  H                                                                                        ##STR107##       CH.sub.2 Cl.sub.2                                                                  188-191                       H   H   H   O  H                                                                                        ##STR108##       CH.sub.2 Cl.sub.2                                                                  201-203                       H   H   H   O  H                                                                                        ##STR109##       CH.sub.2 Cl.sub.2                                                                  141-144                       H   H   H   O  H         CH.sub.2 CF.sub.3 CH.sub.2 Cl.sub.2                                                                  208-211                       H   H   H   O  CH.sub.3  CH.sub.2 C.sub.6 H.sub.5                                                                        CH.sub.2 Cl.sub.2                                                                  68-70                         H   H   H   O  H                                                              t-butyl                                                                           CH.sub.2 Cl.sub.2                                                                 187-192                                                               H   H   H   O  H                                                                                        ##STR110##       CH.sub.2 Cl.sub.2                                                                  216-217                       H   H   H   O  H         CH.sub.2 CH.sub.2N(CH.sub.3).sub.2                                                              CH.sub.2 Cl.sub.2                                                                  146-149                       H   H   H   O  H         CH.sub.2 CH(OCH.sub.3).sub.2                                                                    CH.sub.2 Cl.sub.2                                                                  125-128                       H   H   H   O  H                                                                                        ##STR111##       CH.sub.2 Cl.sub.2                                                                  175-178                       H   H   H   O  H                                                                                        ##STR112##       THF  207- 210                      H   H   H   O  CH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.2 CCH      CH.sub.2 Cl.sub.2                                                                  112-115                       H   H   H   O                                                                                 ##STR113##                 CH.sub.2 Cl.sub.2                                                                  129-133                       H   H   H   O  H                                                                                        ##STR114##       CH.sub.2 Cl.sub.2                                                                  231-234                       H   H   H   O  H                                                                                        ##STR115##       CH.sub.2 Cl.sub.2                                                                    241-242.5                   H   H   H   O  H                                                                                        ##STR116##       CH.sub.2 Cl.sub.2                                                                  242-245                       H   H   H   O  H                                                                                        ##STR117##       CH.sub.2 Cl.sub.2                                                                  200-204                       H   H   H   O  H                                                                                        ##STR118##       CH.sub.2 Cl.sub.2                                                                  221-225                       H   H   H   O  H                                                                                        ##STR119##       CH.sub.2 Cl.sub.2                                                                  183-186                       H   H   H   O  CH.sub.2 C.sub.6 H.sub.5                                                                OH                CH.sub.2 Cl.sub.2                                                                  121-123                       H   H   H   O                                                                                 ##STR120##                 CH.sub.2 Cl.sub.2                                                                  143-146                       H   H   H   O  H                                                                                        ##STR121##       CH.sub.2 Cl.sub.2                                                                  159-161                       H   H   H   O                                                                                 ##STR122##                                                                             OH                CH.sub.2 Cl.sub.2                                                                  131-133                       H   H   H   O  H                                                                                        ##STR123##       THF  173-176                       H   H   H   S  H         CO.sub.2 C.sub.2 H.sub.5                                                                        THF  146-148                       H   H   H   O  H                                                                                        ##STR124##       CH.sub.2 Cl.sub.2                                                                  206-207                       H   H   H   O  H                                                                                        ##STR125##       CH.sub.2 Cl.sub.2                                                                  176-179                       H   H   H   O  H         N(CH.sub.3).sub.2 ether*                                                                             125-128                       H   H   H   O  H                                                                                        ##STR126##       THF**                                                                              149-151                       H   H   H   S  H                                                                                        ##STR127##       THF**                                                                                149-150.5                   H   H   H   O  H         OC.sub.6 H.sub.5  ether*                                                                             159-161                       H   H   H   O  H         OCH.sub.2CO.sub.2 H                                                                             CH.sub.2 Cl.sub.2                                                                  142-145                       __________________________________________________________________________     *diethyl ether                                                                **tetrahydrofuran-                                                       

EXAMPLE 36 Preparation of4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophen-4-amine hydrochloride

2,3-Dimethyl-6,7-dihydro-5H-benzo[b]thiophen-4-one is prepared in themanner described by Napier and Chu [International Journal of SulfurChemistry, A, 1, 62-64 (1971)]. This ketone is converted to4-formylamino-4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophene by themethod described by Kloetzel, Little, and Fish [Journal of OrganicChemistry, 18, 1511-1515 (1953)]. Hydrolysis of this formamidoderivative is accomplished by using the method described in Example 19to afford 4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophen-4-aminehydrochloride.

3-Methyl-6,7-dihydro-5H-benzo[b]thiophen-4-one is prepared similarly andconverted to 3-methyl-4,5,6,7-tetrahydro benzo[b]thiophen-4-aminehydrochloride by the above sequence.

EXAMPLE 37 Preparation of2-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride

2-Methylthiophene is converted to2-methyl-6,7-dihydro-5H-benzo[b]thiophen-4-one by the method describedby Fieser and Kennelly [Journal American Chemical Society, 57, 1611(1925)]. This ketone is further converted to2-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride by themethods cited in Example 36.

EXAMPLE 38 Preparation of2-nitro-N-formyl-4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea

Acetic anhydride (30.8 ml.) is cooled to -10° C. to -12° C. and to thestirred solution is added dropwise 70% nitric acid (4 g. or 44.5 mmol).Over a period of 0.5 hour,N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (7.24 grams or 40mmol) is added and the mixture is allowed to warm to room temperatureover 2.5 hours and poured onto ice-water mixture (200 ml.). Afterstirring overnight, the sticky solid is filtered off and washed wellwith water. The air-dried, dark, sticky solid is triturated with ether(˜20 ml.), and the resulting nitro compound is filtered and washed withether (10 ml.). The product,2-nitro-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, melts at116° C. to 120° C. and weighs 3.25 grams.

Hydrolysis of the above formamide is accomplished by the methoddescribed in Example 19 to afford2-nitro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrogen chloride,melting point > 260° C.; infrared spectrum shows NO₂ bands at 1520 cm⁻ ¹and 1335 cm.sup.⁻¹.

Conversion of the amine hydrogen chloride salt to2-nitro-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is accomplished by themethod described in Example 10. It melts at 211° C. with decompositionafter recrystallization from MeOH.

EXAMPLE 39 Preparation of1-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

By the method of Kloetzel, Little, and Fish [Journal of OrganicChemistry, 18, 1511 (1953)],4,5,6,7-tetrahydro-4-methylbenzo[b]thiophen-4-ol is prepared anddehydrated with fused sodium hydrogen sulfate by heating to afford6,7-dihydro-4-methylbenzo[b]thiophen, boiling point 75°/0.9 Torr. Thisolefin (3 grams) is stirred with 3.9 grams of silver isocyanate in 50ml. of dry ether under N₂ atmosphere at -10° C. and 5.07 grams of iodineis added. After stirring for 1.25 hour at -10° C. to 0° C. and then at10° C. to 15° C. for 1.5 hours, the mixture is filtered overdiatomaceous earth and the filter cake is washed with ether thoroughly.The filtrate is then treated with 2 ml. of 40% aqueous methyl amine toafford 1.62 grams, melting point 122° C. to 123° C., of1-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

EXAMPLE 40 Preparation of1-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

Deiodination of 1-methyl-3-(5-idod-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea is accomplished by treating a methanol mixture of thiscompound with palladium on carbon and magnesium oxide in a Paarhydrogenator at 50 psig. After uptake of the hydrogen is completed, themixture is filtered through diatomaceous earth and filtrate isevaporated to dryness to afford1-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, meltingpoint 135° C. to 145° C.

EXAMPLE 41 Preparation of7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

By the method described in Example 36 (first reference),7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-one is prepared andconverted to 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride, melting point 211.5° C. to 215° C., by the remainingmethods described in Example 36. The amine hydrochloride is converted to7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point184° C. to 189° C. dec., by the method described in Example 10.

EXAMPLE 42 Preparation of6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

By the method described in Example 36 (first reference),6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-one is prepared andconverted to 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride (melting point >300° C.) by the two remaining methodscited in Example 36. The amine hydrochloride is then converted to6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point174° C. to 178° C., by the method outlined in Example 10.

EXAMPLE 43 Preparation of1-methyl-3-(5-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

Diisopropylamine (7.3 grams or 72 mmol) is cooled and stirred in 60 ml.of dry tetrahydrofuran (THF) and 45 ml. (72 mmol) of 1.6N n-butyllithium in hexane is added to <-5° C. Five minutes later a solution of4,5,6,7-tetrahydrobenzo[b]thiophen-4-one, 12 grams of 60 mmol in 30 ml.of THF is added dropwise at 0° C. to -10° C. After stirring for 30minutes at room temperature, 38 grams (270 mmol) of methyl iodide isadded at <30° C. After stirring for 40 hours at room temperature, 100ml. of water is added and the THF is removed in vacuo. The residue isextracted with 3×50 ml. of methylene chloride and the combined extractsare washed with 50 ml. of 2N hydrochloric acid, 50 ml. of 1M sodiumcarbonate, and 50 ml. of brine, respectively. The solution is dried(magnesium sulfate) and evaporated in vacuo to afford 9.46 grams oflight brown oil. The oil is purified by chromatography on a silica-geldry column using 1:1 hexane/methylene chloride to afford 6.9 grams of5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-one. This ketone isconverted to 5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride by the method cited in Example 36 and then the aminehydrochloride is converted to1-methyl-3-(5-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, meltingpoint 173° C. to 182° C., by the method described in Example 1.

Similarly, alkylation of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-one withethyl iodide, propyl iodide, and butyl iodide affords the corresponding5-alkyl ketones, which are converted in the above manner to1-methyl-3-(5-ethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1-methyl-3-(5-propyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, and1-methyl-3-(5-butyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)yrea,respectively.

EXAMPLE 44 Preparation of1-(methoxymethyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

In 150 ml. of methanol, 8.24 grams of4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is stirred and 2.1 grams ofsodium hydroxide pellets followed by 2.31 grams of paraformaldehyde in50 ml. of methanol are added. The mixture is heated at reflux for 10hours and cooled to afford crystals which are collected. The filtrate isevaporated to dryness and the residue is washed with water to afford 6.7grams of solid. Recrystallization of the combined fractions fromacetone-hexane gives 5.3 grams of1-(methoxymethyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, meltingpoint 160° C. to 162° C.

EXAMPLE 45 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl thiourea

A mixture of 13.21 grams of1-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea in 100 ml. of10% sodium hydroxide solution is heated to reflux for 10 minutes andcooled. The solid is collected and dissolved in 95% ethanol and thesolution is evaporated to afford 9 grams of white solid.Recrystallization of this solid from chloroform/hexane affords 8.13grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl thiourea, melting point129° C. to 131° C.

EXAMPLE 46 Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea

A sample of 6 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea isdissolved in 375 ml. of 50% aqueous acetic acid and 75 grams of cericammonium nitrate is added in portions over a 10 minute period withstirring at 25° C. to 35° C. The pale-orange solution is stirred foranother 5 minutes and 100 ml. of water is added. The solution isextracted twice with ethyl acetate (450 ml. and 350 ml.) and thecombined extracts are washed with 100 ml. of water. The organic extractis evaporated to dryness in vacuo and the brown residue is crystallizedfrom methanol to afford 2.37 grams of4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, melting point 237° C. to238° C. dec. Recrystallization from methanol affords purified product,melting point 245° C. to 246° C. dec.

Similarly, 1-methyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea,1-ethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea,1-n-hexyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea,1-n-dodecyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea, and1-phenyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, and theoptical isomers of the 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylureasare prepared by the above procedure starting with the correspondingureas.

Substitution of the ceric ammonium nitrate with silver oxide, chromicanhydride or sodium dichromate also affords the above mentioned 7-oxocompounds. Chromic anhydride in acetic anhydride, followed byhydrolysis, also affords the 7-oxo compounds. The above-mentioned 7-oxoderivatives are also prepared by oxidizing their corresponding7-hydroxycycloalkano[b]thien-4-ylurea in a similar manner.

EXAMPLE 47 Preparation of1,1-dimethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea

A solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine (10.5 g.)in tetrahydrofuran (70 ml.) is added dropwise under nitrogen atomsphereto a solution of dimethylcarbamoyl chloride (6.72 g.) and triethylamine(12.6 g.) in tetrahydrofuran (70 ml.). After stirring for 20 hours, themixture is evaporated to dryness and cold water (100 ml.) is added tothe residue. The solid product is collected and air-dried.Recrystallization from acetone-hexane affords 3.7 g. of1,1-dimethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea, m.p.195° C. to 197° C.

Similarly, dibutylcarbamoyl chloride, dipropylcarbamoyl chloride anddiethylcarbamoyl chloride are used in place of dimethylcarbamoylchloride to afford 1,1-dibutyl-, 1,1-dipropyl-, and1,1-diethyl-3-(4,5,6,7-tetrahydro-7-oxo-benzo[b]thien-4-yl)urea,respectively.

Substitution of the above-mentioned carbamoyl chlorides with thecorresponding thiocarbamoyl chlorides affords the correspondingthioureas.

EXAMPLE 48 Preparation of1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea

Equimolar quantities of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine,dimethylcarbamoyl chloride and sodium hydroxide in water are stirredovernight. The crude product,1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea is collectedand washed well with water. Recrystallization from acetone-hexane-etheraffords pure product, m.p. 117° C. to 120° C.

Similarly, diethyl-, dipropyl-, and dibutylcarbamoyl chloride arereacted with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine to afford1,1-diethyl-, 1,1-dipropyl-, and1,1-dibutyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, respectively.Substitution of the above-mentioned carbamoyl chlorides with thecorresponding thiocarbamoyl chlorides affords the correspondingthioureas.

EXAMPLE 49 Preparation of (+)- and(-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine

A mixture of 145.15 grams of(-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ammonium (R)-N-benzoylglutamate in 900 ml. of water and 50 grams of ice is stirred with 82grams of NaOH in 1265 ml. of water. The mixture is extracted with 700ml. and 500 ml. volumes of diethyl ether and the combined ethersolutions are washed with brine and dried over Na₂ SO₄. The ethersolution is evaporated in vacuo to afford 52.85 grams of a colorlessliquid; [α]_(D) ²⁴ = +57.12° (c, 4.16 in benzene) for the (+)-amine.

Similarly, (+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ammonium(S)-N-benzoyl glutamate was treated with base to afford the (-)-amine,[α]_(D) ²⁵ = - 56.35°° (c, 3.05 in benzene).

EXAMPLE 50 Preparation of (-)- and(+)-N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)formamide

In nitrogen atmosphere, 48.9 grams of 97% formic acid is added dropwise(over 15 minutes) to a stirred mixture of(+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 275 ml. of toluene atbelow 35° C. The mixture is heated at reflux using a Dean-Stark trap toremove water by azeotropic distillation. After 5.5 hours, very littlewater is distilled and thus the mixture is cooled. On cooling, the whiteproduct which crystallizes is collected. Additional product is obtainedwhen the toluene filtrate is concentrated. The combined crops are washedwith 500 ml. of water and then with 150 ml of cold hexane. The yield ofthe (-)-formamide is 60.5 grams, m.p. 132.5° -134° C., [α]_(D) ²⁴ = -119.67° (c, 4.18 in CHCl₃), [α]_(D) ²⁴ = - 126.4° (c, 4.10 in HOAc).

Similarly, the (-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine isconverted to (+)-N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)formamide, m.p.132°-135° C., [α]_(D) ²⁵ = +126.99° (c, 4.08 in HOAc).

EXAMPLE 51 Preparation of(-)-N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)formamide

Ceric ammonium nitrate (726.9 grams) is added portionwise to a stirredsolution of 59.6 grams of(-)-N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)formamide in 1712 ml. of 50%aqueous acetic acid. The addition is completed in half an hour and thetemperature is kept at 25°-28° C. After 15 minutes of stirring, themixture is saturated with NaCl and extracted with CH₂ Cl₂ (2 × 1200 ml.,600 ml.) and the combined extracts are washed with 600 ml. of brine andthen with 250 ml. of water. The water is counter-extracted with 250 ml.of CH₂ Cl₂ and the CH₂ Cl₂ solution is added to the main CH₂ Cl₂solution. The CH₂ Cl₂ solution is evaporated to dryness in vacuo and theresidual dark, gummy residue is stirred with 500 ml. of dry diethylether for 1.5 hour and the large lumps of solid are pulverized. Thetitle compound is then collected, washed with diethyl ether, and dried.This gives 48.65 g., m.p. 130°-136° C., [α]_(D) ²⁴ = 144.4° (c, 0.51 inHOAc).

EXAMPLE 52 Preparation of(+)-N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)formamide

The title compound is prepared in the same manner as the (-) enantiomer(Example 51) and the product melts at 129°-134° C.; [α]_(D) ²⁵.5 = +140.3° (c, 1.06 in HOAc).

EXAMPLE 53 Preparation of(+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride

A mixture of (+)-N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)formamide(52.65 grams) in 525 ml. of 95% ethanol and 525 ml. of 2N HCl is heatedat reflux for 2 hours. The mixture is cooled, filtered through glasswool and the filtrate is evaporated to dryness. The dark solid isdissolved in 180 ml. of water and the insoluble material is collected byfiltration. The filter cake is washed with 70 ml. of water and thecombined solution containing the title compound is used in the nextoperation. A 3 ml. solution is evaporated to dryness and the residue isdissolved in 95% ethanol. The ethanol solution is decolorized withactivated carbon and filtered. The filtrate is evaporated to dryness toafford 0.5 grams of the title compound, m.p. 212°-214° C. (dec.),[α]_(D) ²⁶ = + 13.56° (c, 0.59 in methanol).

Similarly, the (-)-4,5,6,7-tetrahydro-7-oxobenzo-[b]thiophen-4-aminehydrochloride is prepared and used directly in the next operation as asolution.

EXAMPLE 54 Preparation of(-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea

The aqueous solution (280 ml.) of(+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride fromExample 53 is stirred while 40 grams of KOCN in 95 ml. of water is addeddropwise. The mixture is warmed to 70° C. for 1.5 hour and cooled to 10°C. The light brown solid is collected and washed well with 700 ml. ofwater. The product is then stirred with 110 ml. of cold methanol,collected, and washed with 50 ml. of cold methanol to afford 48 grams ofthe title compound, m.p. 247°-249.5° C. (dec.), [α]_(D) ²⁴ = - 97.16°(c, 0.14 in methanol).

EXAMPLE 55 Preparation of(+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea

As described in the preparation of the (-) enantiomer, the titlecompound is prepared in 82% yield; m.p. 243°-246° C. (dec.); [α]_(D)²⁵.5 = + 84.66° (c, 0.19 in methanol).

EXAMPLE 56 Preparation of(-)-4,5,6,7-tetrahydro-7-hydroxybenzo]b]thien-4-ylurea, isomers A and B

In 2.5 liters of ethanol, 34.85 grams of(-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is stirred and 9.8grams of NaBH₄ is added. The mixture is stirred overnight at roomtemperature, 1400 ml. of water is added, and after stirring for 0.5 hourthe ethanol is evaporated in vacuo. The mixture is cooled and 25-30 ml.of acetic acid is added until no more foaming occurs. The mixture isstirred for 0.75 hour, filtered to collect the first crop and this solidis washed with water and air dried. This solid is recrystallized fromacetone and then from acetone/methanol to give 6.75 g. of isomer B ofthe title compound, m.p. 211°-213° C. (dec.), [α]_(D) ²⁵.5 = - 23.23°(c, 3.11 in methanol). This material contains 92% isomer B and 8% isomerA when assayed by high pressure liquid chromatography.

The original mother liquor is evaporated in vacuo, using ethanol to aidin removing water as an azeotrope. The residue is extracted twice withboiling acetone (1400 ml. portions) and the extracts are concentrateduntil crystals formed. A total of 13.1 g. which contains both isomers Aand B is obtained. By preparative high pressure liquid chromatography onsilica gel using a solvent mixture (volume/volume) of 1800 hexane/1000CHCl₃ /425 methanol at a flowrate of 40 ml./minute, 180 milligrams of86% pure isomer A of the title compound is separated. This materialmelts at 162°-167° C. (dec.); [α]_(D) ²⁵.5 = - 93.56° (c, 2.02 inmethanol).

The terms isomer A and isomer B are used for the geometric isomers ofthe title compound as the assignment of the cis and trans configurationshave not been determined unequivocally.

EXAMPLE 57 Preparation of(+)-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea, isomers A and B

In the same manner as described in reducing the(-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, (+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is reduced with NaBH₄ toafford isomer B of the title compound, m.p. 216°-217° C. (dec.), [α]_(D)²⁵.5 = + 18.51° (c, 2.11 in methanol). This isomer is 95% pure by highpressure liquid chromatography. Isomer A of the title compound is alsopurified by high pressure liquid chromatography as a 90-95% purematerial, m.p. 160°-164° C. (dec.), [α]_(D) ²⁴.5 = -91.03° (c, 2.2 inmethanol). The cis and trans configurations for isomers A and B have notbeen determined unequivocally.

EXAMPLE 58 Preparation of (-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride

A sample of 1.02 grams of(dl)-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride istreated with 0.8 grams of sodium hydroxide in 13 ml. of water and thefree amine is extracted with chloroform several times (total volume 200ml.). The chloroform extract is washed with brine, dried over Na₂ SO₄under nitrogen atmosphere, and the solution is evaporated to dryness toafford the liquid amine. The amine is dissolved in 5 ml. of methanol anda solution of 0.75 grams of (+)-tartaric acid in 10 ml. of methanol isadded. The mixture is warmed slightly and allowed to cool to roomtemperature. The crystals are collected and fractionally crystallizedfrom 85-90 ml. of 95% ethanol to afford 0.6 grams of salt. This salt istreated with 0.8 grams of NaOH in 13 ml. of water and the mixture isextracted several times with CHCl₃ (total volume 200 ml.). The combinedextracts are washed with brine, dried over Na₂ SO₄ under nitrogen andthe solution is evaporated to dryness. The residual amine is dissolvedin 10 ml. of acetone and treated with a saturated solution of HCl inisopropyl alcohol (1-2 ml.) until solid no longer forms. The solid titlecompound is collected and dried; melting point 219°-221° C. (dec.);[α]_(D) ²⁸ = -14.23° (c, 0.91 in methanol).

EXAMPLE 59 Preparation of and separation of7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea into the cis andtrans isomers

7-Keto-4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea (0.5 grams, 2.38 mm) issuspended in ethanol (50 ml.) and to the stirred solution is added solidsodium borohydride (0.5 grams, 13.2 mm). After stirring overnight themixture is treated cautiously with 5% aqueous acetic acid (20 ml.).After stirring 15 minutes the solvent is removed, the residue dissolvedin a small volume of methanol and percolated through a 11/2 ' × 13/4silica gel dry column eluting with 20% methanolic methylene chloride.The resulting gum is crystallized from ethyl acetate/methanol to afford66 mg. (13% Y) of the more polar (L.L.C) alcohol (B), melting point 194°C. to 197° C. The mother liquor material is separated into its two majorcomponents 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea by highpressure liquid chromatography on "Spherosil XOA 400" using the solventsystem: hexane (1800 ml.)/methanol (425)/chloroform (1000) flow rate ˜13 ml./min.). This procedure affords the less polar alcohol A (29 mgs.6% yield) melting point, 162° C. to 169° C. (methanol/ethyl acetate),and the more polar alcohol B (50 mg., 10% yield), melting point 197° C.to 198° C.

The following compounds set forth in Table XI below were prepared byreducing an appropriately substituted7-keto-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea with sodium borohydridein ethanol as described immediately hereinabove. Unless otherwiseindicated in Table XI, the products were isolated as a mixture of thecis and trans isomers.

                  TABLE XI                                                        ______________________________________                                         ##STR128##                                                                                             Melting point                                       R.sub.3 R.sub.2           in degrees C.                                       ______________________________________                                        n-C.sub.8 H.sub.17        106-129                                             H       CH.sub.2CHCH.sub.2                                                                              173-176                                             H                                                                             iso-C.sub.3 H.sub.7                                                                   180-187                                                               CH.sub.3                                                                              CH.sub.3          218-225                                             H       CH.sub.3          136-145                                             H       CH.sub.2CCH       176-179                                             CH.sub.3                                                                              OCH.sub.3         179-182                                             H       C.sub.2 H.sub.5   183-188                                             H       OCH.sub.3         158-162                                             H       H                 190-195                                             (mixture of dextrorotatory diastereomers;                                     62 % isomer B)                                                                ______________________________________                                    

EXAMPLE 60 Preparation of2,4-bis[3'-methylureido]-4,5,6,7-tetrahydrobenzo[b]thiophene

2-Nitro-4-amino-4,5,6,7 -tetrahydrobenzo[b]thiophene hydrochloride (0.5grams, 2.13 mmol) is dissolved in concentrated hydrochloric acid (4.3ml.). The stirred solution is treated with stannous chloride dihydrate(2.56 grams, 11.35 mmol) added in portions over a 10 minute period(solution becomes hot). The brown solution is stirred for 3 hours, addedto ice/water (20 ml.), made alkaline with 10% sodium hydroxide and theturbid solution extracted 3 times with methylene chloride (total volumeca. 100 ml.). The combined methylene chloride extracts are washed oncewith brine (20 ml.), dried (sodium sulfate) and evaporated to afford agum. The gum is dissolved in methylene chloride (10 ml.) and ether (10ml.) and the stirred solution treated with a solution of methylisocyanate (0.5 grams, 8.8 mmol) in ether (10 ml.), added over a10-minute period. The mixture is stirred overnight, then evaporated todryness and the residue recrystallized from hot methanol to afford 230mg. (38% yield) of2,4-bis-[3'-methylureido]-4,5,6,7-tetrahydrobenzo[b]thiophene, meltingpoint 233° C. to 234° C.

EXAMPLE 61 Preparation ofN-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine

In the manner described in Example 46,N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is oxidized withceric ammonium nitrate to affordN-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine, melting point118° C. to 120° C. dec. This product is extracted from the reactionmixture with methylene chloride. The use of chromic anhydride in aceticanhydride followed by hydrolysis also affords the identical product.

Using the same work-up procedure, the following oxidants also afford thetitle compound which is isolated and/or analyzed for by spectroscopy(infrared and/or nuclear magnetic resonance). In Table XII below, theoxidant is expressed in terms of moles per mole of substrate.

                  TABLE XII                                                       ______________________________________                                        Oxidant         Conditions      Yield                                         ______________________________________                                        K.sub.2 S.sub.2 O.sub.8 (2M)/AgNO.sub.3                                                     In aqueous acetic 27 %                                          (catalytic)   acid at 50° C.                                           KMnO.sub.4 (3.45M)/                                                                         In aqueous acetic 8 %                                           Ce(NH.sub.4).sub.2 (NO.sub.3).sub.6                                                         acid at less than                                               (catalytic)   35° C.                                                   tert-butyl chro-                                                                            In CCl.sub.4 at room                                                                            33 %                                          mate (4.1M)   temp. for four                                                                hours                                                           CrO.sub.3 . 2 pyridine                                                                      In CH.sub.2 Cl.sub.2 at room                                                                    40 %                                          (11.9M)       temp. overnight                                                 Ce(SO.sub.4).sub.2 . 2H.sub.2 SO.sub.4                                                      In aqueous acetic 60 %                                          (4M)          acid at room temp.                                              H.sub.2 O.sub.2 /V.sub.2 O.sub.5 (cata-                                                     In acetone at 34° C.                                                                     16 %                                          lytic) (acetamide                                                                           overnight                                                       substrate instead                                                             of formamide                                                                  CrO.sub.2 Cl.sub.2 (2M)                                                                     In CH.sub.2 Cl.sub.2 at less                                                                    8.5 %                                         (acetamide sub-                                                                             than 10° C.                                              strate instead                                                                of formamide)                                                                 ______________________________________                                    

EXAMPLE 62 Preparation of4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride

In the manner described in Example 36,N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is hydrolyzedwith 2N hydrochloric acid/ethanol to afford4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride, meltingpoint 230° C. to 232° C. (dec.).

The free amine is obtained by neutralizing the amine hydrochloride inwater with sodium hydroxide solution. It is separated by extraction withCHCl₃ and removal of the CHCl₃ in vacuo affords4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine.

EXAMPLE 63 Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisocyanate and urea

Conversion of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-aminehydrochloride to 4,5,6,7-tetrahydro-7-oxobenzo-[b]thien-4-yl isocyanateis accomplished by heating a toluene mixture of the hydrochloride atreflux temperature while phosgene is introduced. After the mixturebecomes less cloudy, it is cooled and filtered. Evaporation of thefiltrate affords the crude 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisocyanate; IR maximum = 2250 cm.sup.⁻¹.

Addition of NH₃ /CH₃ OH solution to this isocyanate affords4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.

EXAMPLE 64

The following compounds set forth in Table XIII below were prepared byallowing 4,5,6,7-tetrahydro-7-oxobenzo[b]-thiophen-4-amine hydrochlorideto react with RNCX in the presence of an equimolar quantity oftriethylamine in solvents such as aromatic solvents, chlorinatedhydrocarbons, ethers, lower alkyl C₁ -C₄ ketones, or mixtures thereof.

                  TABLE XIII                                                      ______________________________________                                         ##STR129##                                                                                Product                                                                                             Melting                                                                       Point                                                                         in degrees                                 RNCX               R         X     C.                                         ______________________________________                                        CH.sub.3 NCO   CH.sub.3      O     212-215                                    C.sub.2 H.sub.5 NCO                                                                          C.sub.2 H.sub.5                                                                             O     188-190                                     ##STR130##                                                                                   ##STR131##   O     185-188                                    C.sub.6 H.sub.5 CH.sub.2 NCO                                                                 C.sub.6 H.sub.5 CH.sub.2                                                                    O                                                C.sub.2 H.sub.5 NCS                                                                          C.sub.2 H.sub.5                                                                             S                                                CH.sub.3 OCH.sub.2 NCO                                                                       CH.sub.3OCH.sub.2                                                                           O                                                CH.sub.3 OCH.sub.2 NCS                                                                       CH.sub.3OCH.sub.2                                                                           S                                                 ##STR132##                                                                                   ##STR133##   O                                                CH.sub.3 NCS   CH.sub.3      S     161-164                                    ______________________________________                                    

EXAMPLE 65

The following compounds set forth in Table XIV below were prepared byreacting 4,5,6,7-tetrahydro-7-oxobenzo-[b]thien-4-yl isocyanate with theappropriate amines in inert solvents, as described before in Example 35.

                  TABLE XIV                                                       ______________________________________                                         ##STR134##                                                                                 Product                                                         Amines          R.sub.3  R.sub.2                                              ______________________________________                                        NH.sub.2OCH.sub.3                                                                             H        OCH.sub.3                                            NH.sub.2OH      H        OH                                                   CH.sub.3 NHOH   CH.sub.3 OH                                                   CH.sub.3 NHOCH.sub.3                                                                          CH.sub.3 OCH.sub.3                                            CH.sub.2CHCH.sub.2NH.sub.2                                                                    H        CH.sub.2CHCH.sub.2                                    ##STR135##     H                                                                                       ##STR136##                                          (CH.sub.3).sub.2 NH                                                                           CH.sub.3 CH.sub.3                                             C.sub.6 H.sub.5 CH.sub.2 NH.sub.2                                                             H        CH.sub.2C.sub.6 H.sub.5                              C.sub.2 H.sub.5 NH.sub.2                                                                      H        C.sub.2 H.sub.5                                      n-C.sub.4 H.sub.9 NH.sub.2                                                                    H                                                             n-C.sub.4 H.sub.9                                                              ##STR137##     H                                                                                       ##STR138##                                           ##STR139##     H                                                                                       ##STR140##                                           ##STR141##     H                                                                                       ##STR142##                                           ##STR143##     H        CH(CH.sub.3).sub.2                                   ______________________________________                                    

EXAMPLE 66

By the method described in Example 59, the following compounds areprepared as cis and trans mixtures from their corresponding ketoprecursors:

Optically active isomers of7-hydroxy-4,5,6,7-tetrahyrobenzo[b]thien-4-ylurea,1-methyl-3-(7-hyroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1-ethyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1,1-dimethyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1-methoxy-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1-methyl-1-methoxy-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]-thien-4-yl)urea,1-hydroxy-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]-thien-4-yl)urea,1-hydroxy-1-methyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1-methoxymethyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea,1-allyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-urea, and1-(2-propynyl)-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

EXAMPLE 67 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

A sample of 6,7-dihydrobenzo[b]thiophene is stirred in the cold in 96%sulfuric acid containing 4- 6 mole equivalents of urea. After 1 hour themixture is poured on ice and the organic phase is removed. Evaporationof the organic phase to dryness in vacuo affords4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea.

EXAMPLE 68 Preparation of 4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea

A 1 gram sample of 4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene isstirred in the cold for several hours in thionyl chloride (5 ml.) andthe mixture is evaporated to dryness. The crude4-chloro-4,5,6,7-tetrahydrobenzo[b]thiophene is then added to a mixtureof urea (1- 5 mole-equivalents) in dimethylformamide and diisopropylethylamine. The mixture is warmed, after several hours, to 50° C. andafter 4 hours is poured on ice and the product,4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, is collected by filtration.

EXAMPLE 69 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

A sample of 6,7-dihydrobenzo[b]thiophene is stirred with silverisocyanate and iodine as described in Example 39 and the resultingproduct, 5-iodo-4,5,6,7-tetrahydrobenzo[b]-thien-4-yl isocyanate istreated with concentrated ammonia solution to afford5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea. This latter product isthen reduced in the manner described in Example 40 to afford4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea.

The following products set forth in Table XV below were also obtained byreacting 5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate with R₂R₃ NH to afford the corresponding iodo ureas, which were thenhydrogenated in the above manner to give compounds of the formula:

                  TABLE XV                                                        ______________________________________                                         ##STR144##                                                                   R.sub.3              R.sub.2                                                  ______________________________________                                        H                    CH.sub.3                                                 H                    C.sub.2 H.sub.5                                          H                    CH(CH.sub.3).sub.2                                       CH.sub.3             CH.sub.3                                                 H                    OH                                                       H                    OCH.sub.3                                                CH.sub.3             OH                                                       CH.sub.3             OCH.sub.3                                                ______________________________________                                    

When allyl amine and 2-propynyl amine are used to give 1-allyl- or1-(2-propynyl)-3-(5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, theresulting iodo ureas are deiodinated with tributyl tin hydride (Bu₃SnH). This reducing agent (Bu₃ SnH) can also be used to deiodinate theseaforementioned iodo ureas, while use of Zn/HCl gives the desired ureasand polymeric material.

EXAMPLE 70 Preparation of1-(2-propynyl)-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea.

A sample of 11.5 grams of4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is dissolved in 100 ml.of CH₂ Cl₂ and the solution is added dropwise over 0.5 hours to 11 gramsof carbonyl diimidazole stirred in 50 ml. of CH₂ Cl₂. The mixture isstirred at room temperature for an hour and then added over a 0.5 hourperiod to 3.74 grams of 2-propargylamine in 50 ml. of CH₂ Cl₂. After 3hours, the crude title product is collected to afford 9.8 grams, m.p.170°-183° C. Recrystallization from acetone-hexane gives 4.1 grams oftitle compound, m.p. 197°-199° C.

Similarly, when thiocarbonyl diimidazole is used instead of carbonyldiimidazole, the corresponding1-(2-propynyl)-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]-thien-4-yl)thioureais obtained.

When the1-(1-imidazolyl)-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea isallowed to react with methyl methoxyamine, the product is1-methoxy-1-methyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea,m.p. 130°-136° C.

Other amines (R₂ R₃ NH) are used in the same manner to prepare thecorresponding ureido compounds as listed in Table XVI below. Unlessotherwise indicated in Table XVI, the products were isolated as thedl-racemates.

                  TABLE XVI                                                       ______________________________________                                         ##STR145##                                                                                               Melting point                                     R.sub.3                                                                              R.sub.2              in degrees C.                                     ______________________________________                                        H      CH.sub.2CHCH.sub.2   171-174                                           H      OCH.sub.3            185-188.5                                         iso-C.sub.3 H.sub.7                                                                  198-200                                                                CH.sub.3                                                                             CH.sub.3             195-197                                           CH.sub.3                                                                             OCH.sub.3            126-129                                           CH.sub.3                                                                             OH                   163-165.5                                         H                                                                             n-C.sub.8 H.sub.17                                                                   105-108                                                                H                                                                                     ##STR146##          204-207                                           H      H                    243-246                                                  (dextrorotatory enantiomorph)                                          H      H                    247-249.5                                                (levorotatory enantiomorph)                                                   4,5,6,7-tetrahydro-2-bromo-                                            7-oxobenzo[b]thien-4-ylurea                                                          252-253                                                                H      n-C.sub.10 H.sub.21  104-107                                           H      n-C.sub.12 H.sub.25  83-86,                                                                        116-118                                           H      n-C.sub.14 H.sub.28  88-90,                                                                        114-116                                           ______________________________________                                    

EXAMPLE 71 Preparation of1-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea

5,6,7,8-Tetrahydro-4H-cyclohepta[b]thiophen-4-one is converted toN-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)formamide, m.p.164°-166° C., by the method of Kloetzel et al., Journal of OrganicChemistry 18, 1511 (1953). Hydrolysis of the formamide is accomplishedby refluxing for one hour in 1N hydrochloric acid and evaporating todryness to afford 5,6,7,8-tetrahydro-4H-cyclohepta[ b]thiophen-4-aminehydrochloride, m.p. 233°-236° C. dec. The amine hydrochloride is thenallowed to react with methyl isocyanate in dry tetrahydrofuran assolvent in the presence of a stoichiometric equivalent of triethylamineto afford1-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea, m.p.220°-222° C.

Similarly, by substituting ethyl isothiocyanate for methyl isocyanate inthe above procedure there is obtained1-ethyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)-2-thiourea,m.p. 117°-120° C.

EXAMPLE 72 Preparation of5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea

A mixture of 50 grams of5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride in 100ml. of water is stirred at about 15° C. and a solution of 23.1 grams ofpotassium cyanate in 100 ml. of water is added dropwise. Aftercompletion of the addition, the mixture is warmed slowly to 70°-75° C.and held there for 1 hour. The mixture is cooled and the white solid iscollected by filtration and washed with water. The solid is air-dried,pulverized, and washed with acetonitrile. Upon drying, this crudeproduct is treated with hot acetone whereby there is obtained5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea, m.p. 217° C. dec.

EXAMPLE 73 Preparation of1-(methoxymethyl)-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea

In 150 ml. of methanol is stirred 8.24 grams of5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea and 2.1 grams ofsodium hydroxide pellets followed by 2.31 grams of paraformaldehyde in50 ml. of methanol. The mixture is heated at reflux for 10 hours andcooled to afford crystals which are collected. The filtrate isevaporated to dryness and the residue is washed with water to affordmore solid. Recrystallization of the combined fractions fromacetone-hexane gives1-(methoxymethyl)-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]-thien-4-yl)urea,m.p. 197°-201° C. dec.

EXAMPLE 74 Preparation of5,6,7,8-tetrahydro-4H-8-oxocyclohepta[b]thien-4-ylurea

In 375 ml. of 50% aqueous acetic acid is dissolved 6 grams of5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea, and 75 grams of cericammonium nitrate is added portionwise over a 10 minute period withstirring at 25°-35° C. The pale orange solution is stirred for anotherfive minutes and 100 ml. of water is added. The solution is extractedtwice with ethyl acetate (450 ml. and 350 ml.) and the combined extractsare washed with 100 ml. of water. The organic extract is evaporated todryness in vacuo and the brown residue is recrystallized from methanolto afford 5,6,7,8-tetrahyro-4H-8-oxocyclohepta[b]thien-4-ylurea, m.p.246°-248° C. dec.

EXAMPLE 75 Growth Enhancement and Feed Efficiency Evaluations in SheepGiven an Implant Containing Test Compound

To determine the effect of a 4,5,6,7-tetrahydrobenzo[b]thien-4-ylureacompound on sheep, Wether lambs are randomly allotted to pens in groupsof six. The sheep are weighed and permitted food and water ad libitum.The feed is weighed daily, and uneaten feed from the previous day iscollected and weighed. Test lambs receive the same unmedicated diet ascontrol animals, but test animals receive one or more subcutaneousimplants containing test compound at the base of the ear. Theformulation of the implant used is given below. At the end of thesix-week treatment period, the lambs are again weighed, and total feedconsumed is calculated.

In these tests, six replicates of six lambs each per treatment are usedand each animal receives from about 11 mg. to 105 mg. of test compound.

Average six-week weight gains are presented in Table XVII and feed perpound of gain is presented in Table XVIII. From these data it can beseen that lambs implanted with 11 mg. or 99 mg. of test compound showedapproximately a 10% increase in weight gain over untreated controlssix-weeks after implantation. Feed utilization for the same period wasalso improved by about 5% over untreated controls.

    ______________________________________                                        LAMB DIET                                                                                                  %                                                Ground Corn Cob              15.0                                             Ground Yellow Corn           48.0                                             Soybean Oil Meal (49%)       10.0                                             Dehydrated Alfalfa Meal      15.0                                             Molasses                     10.0                                             Iodized Salt                 0.5                                              Dicalcium Phosphate          1.0                                              Premix                       0.5                                                                           100.0                                            PREMIX FOR ONE TON                                                            Tra-Min No. 3.sup.(1)    454     grams                                        Vitamin A (30,000 μ/g)                                                                              133     grams                                        Vitamin D.sub.3 (200,000 μ/g)                                                                       5       grams                                        Corn Oil                 100     grams                                        Ground Corn              3848    grams                                                                 4540                                                 .sup.(1) Tra-min No. 3:                                                                     Calcium          21.00%                                                       Manganese        12.50%                                                       Iron             6.00%                                                        Zinc             5.00%                                                        Copper           0.65%                                                        Iodine           0.35%                                                        Cobalt           0.25%                                          Pellet Implant                                                                4,5,6,7-Tetrahydrobenzo[b]thien-                                                                        11.0    mg.                                          4-ylurea                                                                     Glyceryl 12-hydroxystearate                                                                             10.50   mg.                                         Magnesium stearate        0.50    mg.                                                                   22.00   mg.                                         ______________________________________                                    

                                      TABLE XVII                                  __________________________________________________________________________    Average 6-Week Weight Gain (kg.)/Lamb                                                  Drug   Replication                                                   Treatment                                                                              Implants a/                                                                          1   2   3   4   5   6   AV.                                   __________________________________________________________________________    Control  0       8.50                                                                             8.70                                                                              9.93                                                                              6.50                                                                              7.03                                                                              6.75                                                                              7.90                                  4,5,6,7-tetra-                                                                         1      11.25                                                                             9.32                                                                              9.20                                                                              8.63                                                                              8.05                                                                              6.68                                                                              8.86                                  hydrobenzo[b]-                                                                thien-4-ylurea                                                                         9      10.83                                                                             9.60                                                                              8.75                                                                              7.20                                                                              8.53                                                                              7.20                                                                              8.69                                  __________________________________________________________________________     a/ Approximate weight: 22 mg. each    Composition: 50% drug + 50% carrier

                                      TABLE XVIII                                 __________________________________________________________________________    Average 6-Week Feed/Gain per Pen                                                       Number of                                                                     Drug   Replication                                                   Treatment                                                                              Implants a/                                                                          1   2   3   4   5   6   AV.                                   __________________________________________________________________________    Control  0      7.88                                                                              6.77                                                                              7.41                                                                              8.82                                                                              9.18                                                                              8.16                                                                              8.04                                  4,5,6,7-tetra-                                                                         1      6.63                                                                              6.58                                                                              7.41                                                                              8.21                                                                              8.05                                                                              8.49                                                                              7.57                                  hydrobenzo[b]-                                                                thien-4-ylurea                                                                         9      6.51                                                                              6.75                                                                              7.80                                                                              8.38                                                                              7.56                                                                              7.97                                                                              7.49                                  __________________________________________________________________________     a/ Approximate weight: 22 mg. each    Composition: 50% drug + 50% carrier

EXAMPLE 76 Growth Enhancement and Feed Efficiency Improvement in SheepFed Levels of Test Compounds

To determine the effect of feeding experimental compounds on sheepperformance, Wether lambs are randomly allotted to pens in groups ofsix. The sheep are weighed and permitted feed and water ad libitum. Thefeed is weighed daily, and uneaten feed from the previous day iscollected and weighed. Test lambs receive the same diet as controlanimals but with the addition of experimental compound at aconcentration of either 15 or 60 ppm. At the end of the six-weektreatment period, the lambs are again weighed, and total feed iscalculated.

In these tests, five replicates of six lambs each per treatment areused. Experimental compounds are as follows:

A - 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea

B - 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea

Average daily gains for the six-week period are presented in Table XIXand feed per unit of gain is presented in Table XX. From these data itcan be seen that lambs fed either 15 or 60 ppm of the test compoundsshowed improvements in weight gain and feed efficiency over untreatedcontrols.

                  TABLE XIX                                                       ______________________________________                                        Average Daily Gain (kg)/Lamb                                                          Level  Replication                                                    Treatment (ppm)    1      2    3    4    5    av.                             ______________________________________                                        Control   --       0.175  0.223                                                                              0.169                                                                              0.159                                                                              0.185                                                                              0.182                           Compound A                                                                              15       0.190  0.187                                                                              0.186                                                                              0.174                                                                              0.195                                                                              0.186                           Compound A                                                                              60       0.211  0.250                                                                              0.200                                                                              0.193                                                                              0.189                                                                              0.208                           Compound B                                                                              15       0.187  0.208                                                                              0.218                                                                              0.186                                                                              0.210                                                                              0.202                           Compound B                                                                              60       0.216  0.207                                                                              0.237                                                                              0.189                                                                              0.190                                                                              0.208                           ______________________________________                                    

                  TABLE XX                                                        ______________________________________                                        Six-Week Feed/Gain                                                                    Level  Replication                                                    Treatment (ppm)    1      2    3    4    5    av.                             ______________________________________                                        Control   --       7.111  5.563                                                                              6.692                                                                              7.414                                                                              6.392                                                                              6.635                           Compound A                                                                              15       6.777  6.174                                                                              6.158                                                                              7.626                                                                              6.319                                                                              6.611                           Compound A                                                                              60       6.250  5.539                                                                              6.040                                                                              6.507                                                                              6.403                                                                              6.148                           Compound B                                                                              15       6.785  6.067                                                                              5.344                                                                              6.795                                                                              6.089                                                                              6.216                           Compound B                                                                              60       6.116  6.263                                                                              5.144                                                                              6.723                                                                              6.506                                                                              5.151                           ______________________________________                                    

EXAMPLE 77

The following tests were conducted to evaluate the ability of4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea to promote growth in chicks.

In these tests day-old chicks are placed in heated cages and given feedand water ad libitum. In each test there are 5 male and 5 female chicksper cage and three cages per treatment are used. Treatments consist of abasal diet plus 1,3 or 9 ppm. of test compound. The chicks are weighedat the beginning and end of the experiment. Feed consumption isdetermined for the experimental period which is 13 days beginning whenthe chicks are one day old. The basal diet employed and results obtainedare reported below.

    ______________________________________                                        Chick Basal Diet                                                              Ground yellow corn   53.45%                                                   Soybean oil meal (49%)                                                                             28.0                                                     Menhaden fish meal (60%)                                                                           5.0                                                      Corn gluten meal (60%)                                                                             5.0                                                      Dehydrated alfalfa meal (17%)                                                                      2.0                                                      Stabilized fat       4.0                                                      Dicalcium phosphate  1.2                                                      Ground limestone     0.5                                                      Sodium chloride      0.3                                                      *Tra-Min No. 3       0.05                                                     **Vitamin premix     0.5                                                                           100.00                                                   **VITAMIN PREMIX FOR 1-TON                                                    DL methionine        453.6     grams                                          BHT                  113.6                                                    Vitamin A (30,000 μ/g)                                                                          100.0                                                    Vitamin D.sub.3 (200,000 μ/g)                                                                   5.0                                                      Vitamin E (20,000 μ/lb.)                                                                        45.4                                                     Riboflavin           4.0                                                      Niacinamide          25.0                                                     Ca. Pantothenate     8.0                                                      Vitamin K (menadione)                                                                              1.0                                                      Parvo (10%), folic acid                                                                            13.0                                                     Choline chloride (50%)                                                                             908.0                                                    Proferm (20 mg/lb.), B.sub.12                                                                      227.0                                                    Corn oil             50.0                                                     Fine ground corn     2582.4                                                                        4536.0                                                   *Tra-Min No. 3            1 lb/Ton Furnishes                                  ______________________________________                                        Manganese   12.50%        62.5 ppm                                            Iron        6.00%         30.0                                                Zinc        5.00          25.0                                                Copper      0.65%         3.25                                                Iodine      0.35%         1.75                                                Cobalt      0.25%         1.25                                                Calcium     15.30% Min.                                                                   18.35% Max.                                                       ______________________________________                                    

    __________________________________________________________________________    Chick Tests                                                                   Average 13-day Chick/Gain (g)                                                          Level                                                                             Experiment           Percent                                              (ppm)                                                                             1928                                                                              1929                                                                              1930                                                                              1931                                                                              AV. Improvement                                  __________________________________________________________________________      Control                                                                              --  189 175 180 188 183 --                                             4,5,6,7-                                                                             1   181 193 182 200 189 3.3                                            tetrahydro-                                                                   benzo[b]-                                                                            3   199 186 197 198 195 6.6                                            thien-4-                                                                      ylurea 9   190 198 191 191 193 5.5                                          __________________________________________________________________________

    __________________________________________________________________________    Average 13-day Feed/Gain                                                               Level                                                                             Experiment          Percent                                      Treatment                                                                              (ppm)                                                                             1928                                                                              1929                                                                              1930                                                                              1931                                                                              AV. Improvement                                  __________________________________________________________________________      Control                                                                              --  1.54                                                                              1.52                                                                              1.46                                                                              1.48                                                                              1.50                                                                              --                                             4,5,6,7-                                                                             1   1.48                                                                              1.45                                                                              1.49                                                                              1.44                                                                              1.46                                                                              2.7                                            tetrahydro-                                                                   benzo[b]-                                                                            3   1.47                                                                              1.40                                                                              1.44                                                                              1.40                                                                              1.43                                                                              4.7                                            thien-4-                                                                      ylurea 9   1.45                                                                              1.45                                                                              1.46                                                                              1.40                                                                              1.44                                                                              4.0                                          __________________________________________________________________________

EXAMPLE 78 Preparation of1-(methoxymethyl)-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea

A mixture of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]-thien-4-yl urea (4 g.,18.87 mmole), sodium hydroxide (0.969 g., 24.22 mmole), paraformaldehyde(1.038 g., 34.6 mmole) and methanol (94 ml.) is stirred and heated atreflux under a nitrogen atmosphere for 23 hours. The mixture is allowedto cool and excess solid carbon dioxide is added. Evaporation in vacuoaffords a solid which is stirred with water (50 ml.) for 2 hours,filtered and air dried to furnish 3.16 g., of the title compound (65%yield) m.p. 157°-159° C. dec. Recrystallization from hot acetone givesthe analytical specimen 160°-161° C. dec.

EXAMPLE 79 Preparation of1-(methoxymethyl)-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea

A solution of1-(methoxymethyl)-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea(0.35 g., 1.37 mmole) in acetone (40 ml.) is treated with manganesedioxide (3.5 g.). After 2 hours stirring the reaction mixture isfiltered through celite, the cake washed thoroughly with acetone and thefiltrate and washings evaporated to furnish 0.32 g. on 90.7% yield ofthe title compound as a crystalline solid, m.p. 155°-158° C.Recrystallization from hot acetone affords the analytical sample, m.p.159°-162° C.

I claim:
 1. A method for improving the feed efficiency and enhancing thegrowth rate of veterinary homothermic animals which comprisesadministering to said animals an effective amount of a compound selectedfrom the group consisting of those of the formulae: ##STR147## wherein Xis oxygen or sulfur; n is the integer 1 or 2; Y is a divalent radicalselected from the group consisting of those of the formulae: ##STR148##R₁ is hydrogen or alkyl C_(1--C) ₄ ; R₃ is selected from the groupconsisting of hydrogen, alkyl C₁ -C₄, cycloalkyl C₃ -C₆, allyl,2-propynyl, benzyl and β-phenethyl; R₄ is hydrogen or alkyl C₁ -C₄ ; R₅is hydrogen, chloro, bromo or iodo; R₆ is hydrogen or alkyl C₁ -C₄ ; R₂is selected from the group consisting of the substituents listed in thefollowing table:

    ______________________________________                                               hydrogen                                                                      alkyl C.sub.1- C.sub.8                                                        cycloalkyl C.sub.3- C.sub.6                                                   allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1- C.sub.6                                                       allyloxy                                                                      methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                  OCH.sub.2CO.sub.2 H                                                           CO.sub.2 C.sub.2 H.sub.5                                                       ##STR149##                                                                    ##STR150##                                                                    ##STR151##                                                                    ##STR152##                                                                    ##STR153##                                                                    ##STR154##                                                                    ##STR155##                                                            ______________________________________                                    

wherein R is alkyl C₁ -C₄, m is 0, 1 or 2, and Q is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquniolino and themoiety of the formula: ##STR156##
 2. A method according to claim 1wherein said compound is orally administered to said animals in anamount equivalent to between 0.0001% and 0.08% by weight of the animalfeed.
 3. A method according to claim 1 wherein said compound isparenterally administered as one or more subcutaneous implants beneaththe skin of said animal and said implants being sufficient to provide adaily drug release of from 0.0005% mg. to 0.2 mg. of said compound perkg. of animal body weight.wherein R is alkyl C₁ -C₄, m is 0, 1 or 2, andQ is selected from the group consisting of the substituents listed inthe following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR157##
 4. A method for improving the feedefficiency and enhancing the growth rate of veterinary homothermicanimals which comprise administering to said animals an effective amountof a compound selected from the group consisting of the dextrorotatoryenantiomorph, the levorotatory enantiomorph, and the racemic mixturethereof of a compound of the formula: ##STR158## wherein X is oxygen orsulfur; n is the integer 1 or 2; R₁ is hydrogen or alkyl C₁ -C₄ ; R₃ isselected from the group consisting of hydrogen, alkyl C₁ -C₄, cycloalkylC₃ -C₆, allyl, 2-propynyl, benzyl and β-phenethyl; R₄ is hydrogen oralkyl C₁ -C₄ ; R₅ is hydrogen, chloro, bromo or iodo; R₆ is hydrogen oralkyl C₁ -C₄ ; R₂ is selected from the group consisting of thesubstituents listed in the following table:

    ______________________________________                                               hydrogen                                                                      alkyl C.sub.1- C.sub.8                                                        cycloalkyl C.sub.3- C.sub.6                                                   allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1- C.sub.6                                                       allyloxy                                                                      methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                  OCH.sub.2CO.sub.2 H                                                           CO.sub.2 C.sub.2 H.sub.5                                                       ##STR159##                                                                    ##STR160##                                                                    ##STR161##                                                                    ##STR162##                                                                    ##STR163##                                                                    ##STR164##                                                                    ##STR165##                                                            ______________________________________                                    

wherein R is alkyl C₁ -C₄, m is 0, 1 or 2, and Q is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR166##
 5. The method according to claim 4wherein the compound is the racemic mixture wherein X is oxygen, n is 1,and R₁, R₂, R₃, R₄, R₅ and R₆ are hydrogen;dl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.
 6. The method according toclaim 4 wherein the compound is the dextrorotatory enantiomorph whereinX is oxygen, n is 1, and R₁, R₂, R₃, R₄, R₅ and R₆ are hydrogen;d-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.
 7. The method according toclaim 4 wherein the compound is the levorotatory enantiomorph wherein Xis oxygen, n is 1, and R₁, R₂, R₃, R₄, R₅ and R₆ are hydrogen,l-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.
 8. The method according toclaim 4 wherein the compound is the racemic mixture wherein X is oxygen,n is 1, R₁ and R₂ are hydrogen, R₃ is methyl, and R₄, R₅ and R₆ arehydrogen; dl-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. 9.The method according to claim 4 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is methoxy, R₃is methyl, and R₄, R₅ and R₆ are hydrogen;dl-1-methoxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. 10.The method according to claim 4 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ isethyl, and R₄, R₅ and R₆ are hydrogen;dl-1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
 11. The methodaccording to claim 4 wherein the compound is the racemic mixture whereinX is oxygen, n is 1, R₁ is hydrogen, R₂ is methoxy, and R₃, R₄, R₅ andR₆ are hydrogen;dl-1-methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
 12. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is hydroxy, R₃ ismethyl, and R₄, R₅ and R₆ are hydrogen;dl-1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. 13.The method according to claim 4 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ is hydrogen; R₂ is hydroxy, andR₃, R₄, R₅ and R₆ are hydrogen;dl-1-hydroxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
 14. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen; R₂ is methoxymethyl, andR₃, R₄, R₅ and R₆ are hydrogen;dl-1-methoxymethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
 15. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ is 2-propynyl,and R₄, R₅ and R₆ are hydrogen;dl-1-(2-propynyl)-3-(4,5,6,7-tetrahydrobenzo[b]-thien-4yl)urea.
 16. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ is allyl, andR₄, R₅ and R₆ are hydrogen;dl-1-allyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
 17. The methodaccording to claim 4 wherein the compound is the racemic mixture whereinX is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ is isopropyl, and R₄, R₅and R₆ are hydrogen;dl-1-isopropyl-3-(4,5,6,7-tetrahydrobenzo[b]-thien-4yl)urea.
 18. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen, R₂ and R₃ are methyl, andR₄, R₅ and R₆ are hydrogen;dl-1,1-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
 19. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 2, R₁ and R₂ are hydrogen, R₃ is methyl, andR₄, R₅ and R₆ are hydrogen;dl-1-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta-[b]thien-4-yl)urea. 20.The method according to claim 4 wherein the compound is the racemicmixture wherein X is oxygen, n is 2, R₁ and R₂ are hydrogen, R₃ isethyl, and R₄, R₅ and R₆ are hydrogen;dl-1-ethyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta-[b]thien-4-yl)urea. 21.The method according to claim 4 wherein the compound is the racemicmixture wherein X is oxygen, n is 2, and R₁, R₂, R₃, R₄, R₅ and R₆ arehydrogen; dl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea.
 22. Themethod according to claim 4 wherein the compound is the racemic mixturewherein X is oxygen, n is 2, R₁ is hydrogen, R₂ is methoxymethyl, andR₃, R₄, R₅ and R₆ are hydrogen;dl-1-methoxymethyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea.23. A method for improving the feed efficiency and enhancing the growthrate of veterinary homothermic animals which comprises administering tosaid animals an effective amount of a compound selected from the groupconsisting of the dextrorotatory enantiomorph, the levorotatoryenantiomorph, and the racemic mixture thereof of a compound of theformula: ##STR167## wherein X is oxygen or sulfur; n is the integer 1 or2; R₁ is hydrogen or alkyl C₁ -C₄ ; R₃ is selected from the groupconsisting of hydrogen, alkyl C₁ -C₄, cycloalkyl C₃ -C₆, allyl,2-propynyl, benzyl and β-phenethyl; R₄ is hydrogen or alkyl C₁ -C₄ ; R₅is hydrogen, chloro, bromo or iodo; R₆ is hydrogen or alkyl C₁ -C₄ ; R₂is selected from the group consisting of the substituents listed in thefollowing table:

    ______________________________________                                               hydrogen                                                                      alkyl C.sub.1C.sub.8                                                          cycloalkyl C.sub.3C.sub.6                                                     allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1C.sub.6                                                         allyloxy                                                                      methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                  OCH.sub.2CO.sub.2 H                                                           CO.sub.2 C.sub.2 H.sub.5                                                       ##STR168##                                                                    ##STR169##                                                                    ##STR170##                                                                    ##STR171##                                                                    ##STR172##                                                                    ##STR173##                                                                    ##STR174##                                                            ______________________________________                                    

wherein R is alkyl C₁ -C₄, m is 0, 1 or 2, and Q is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR175##
 24. The method according to claim 21wherein the compound is the racemic mixture wherein X is oxygen, n is 1,and R₁, R₂, R₃, R₄, R₅ and R₆ are hydrogen;dl-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.
 25. The methodaccording to claim 23 wherein the compound is the dextrorotatoryenantiomorph wherein X is oxygen, n is 1, and R₁, R₂, R₃, R₄, R₅ and R₆are hydrogen; d-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.
 26. Themethod according to claim 23 wherein the compound is the levorotatoryenantiomorph wherein X is oxygen, n is 1, and R₁, R₂, R₃, R₄, R₅ and R₆are hydrogen; 1-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.
 27. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ is methyl, andR₄, R₅ and R₆ are hydrogen;dl-1-methyl-3-(4,5,6,7tetrahydro-7-oxobenzo[b]-thien-4-yl)urea.
 28. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ is ethyl, andR₄, R₅ and R₆ are hydrogen;dl-1-ethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]-thien-4-yl)urea.
 29. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is methoxymethyl, andR₃, R₄, R₅ and R₆ are hydrogen;dl-1-methoxymethyl-3-(4,5,6,7-tetrahydro-oxobenzo[b]thien-4-yl)urea. 30.The method according to claim 23 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ is2-propynyl, and R₄, R₅ and R₆ are hydrogen;dl-1-(2-propynyl)-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea.31. The method according to claim 23 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ isallyl, and R₄, R₅, and R₆ are hydrogen;dl-1-allyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea.
 32. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is methoxy, R₃ ismethyl, and R₄, R₅, and R₆ are hydrogen,dl-1-methoxy-1-methyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea.33. The method according to claim 23 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is hydroxy andR₃, R₄, R₅ and R₆ are hydrogen;dl-1-hydroxy-3(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea.
 34. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is hydroxy, R₃ ismethyl, and R₄, R₅ and R₆ are hydrogen;dl-1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea.35. The method according to claim 23 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ is methoxy, andR₃, R₄, R₅ and R₆ are hydrogen;dl-1-methoxy-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4yl)urea.
 36. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 1, R₁ is hydrogen, R₂ and R₃ are methyl, andR₄, R₅ and R₆ are hydrogen;dl-1,1-dimethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo-[b]thien-4-yl)urea. 37.The method according to claim 23 wherein the compound is the racemicmixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ isisopropyl, and R₄, R₅ and R₆ are hydrogen;dl-1-isopropyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea. 38.The method according to claim 23 wherein the compound is thelevorotatory enantiomorph wherein X is oxygen, n is 2, and R₁, R₂, R₃,R₄, R₅ and R₆ are hydrogen;1-5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thien-4-ylurea.
 39. Themethod according to claim 23 wherein the compound is the racemic mixturewherein X is oxygen, n is 2, and R₁, R₂, R₃, R₄, R₅ and R₆ are hydrogen;dl-5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thien-4ylurea.
 40. A methodfor improving the feed efficiency and enhancing the growth rate ofveterinary homothermic animals which comprises administering to saidanimals an effective amount of a compound selected from the groupconsisting of the cis-dextrorotatory enantiomorph, the cis-levorotatoryenantiomorph, the racemic mixture of the cis-enantiomorphs, thetrans-dextrorotatory enantiomorph, the trans-levorotatory enantiomorph,and the racemic mixture of the trans-enantiomorphs of a compound of theformula: ##STR176## wherein X is oxygen or sulfur; n is the integer 1 or2; R₁ is hydrogen or alkyl C₁ -C₄ ; R₃ is selected from the groupconsisting of hydrogen, alkyl C₁ -C₄, cycloalkyl C₃ -C₆, allyl,2-propynyl, benzyl and β-phenethyl; R₄ is hydrogen or alkyl C₁ -C₄ ; R₅is hydrogen, chloro, bromo or iodo; R₆ is hydrogen or alkyl C₁ -C₄ ; R₂is selected from the group consisting of the substituents listed in thefollowing table:

    ______________________________________                                               hydrogen                                                                      alkyl C.sub.1C.sub.8                                                          cycloalkyl C.sub.3C.sub.6                                                     allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1C.sub.6                                                         allyloxy                                                                      methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                  OCH.sub.2CO.sub.2 H                                                           CO.sub.2 C.sub.2 H.sub.5                                                       ##STR177##                                                                    ##STR178##                                                                    ##STR179##                                                                    ##STR180##                                                                    ##STR181##                                                                    ##STR182##                                                                    ##STR183##                                                            ______________________________________                                    

wherein R is alkyl C₁ -C₄, m is 0, 1 or 2, and Q is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR184##
 41. The method according to claim 40wherein the compound is the cis-racemic mixture wherein X is oxygen, nis 1, and R₁, R₂, R₃, R₄, R₅ and R₆ are hydrogen;dl-cis-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea.
 42. Themethod according to claim 40 wherein the compound is the trans-racemicmixture wherein X is oxygen, n is 1, and R₁, R₂, R₃, R₄, R₅ and R₆ arehydrogen; dl-trans-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea.43. The method according to claim 40 wherein the compound is thecis-dextrorotatory enantiomorph wherein X is oxygen, n is 1, and R₁, R₂,R₃, R₄, R₅ and R₆ are hydrogen;d-cis-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea.
 44. The methodaccording to claim 40 wherein the compound is the cis-levorotatoryenantiomorph wherein X is oxygen, n is 1, and R₁, R₂, R₃, R₄, R₅ and R₆are hydrogen; 1-cis-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4ylurea.45. The method according to claim 40 wherein the compound is thetrans-dextrorotatory enantiomorph wherein X is oxygen, n is 1, and R₁,R₂, R₃, R₄, R₅ and R₆ are hydrogen;d-trans-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea.
 46. Themethod according to claim 40 wherein the compound is thetrans-levorotatory enantiomorph wherein X is oxygen, n is 1, and R₁, R₂,R₃, R₄, R₅ and R₆ are hydrogen;1-trans-4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea.
 47. Themethod according to claim 40 wherein the compound is the cis-racemicmixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen, R₃ ismethyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-methyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.48. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ arehydrogen, R₃ is methyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-methyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.49. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen,R₃ is ethyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-ethyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.50. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ arehydrogen, R₃ is ethyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-ethyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.51. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ andR₃ are methyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1,1,-dimethyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4yl)urea52. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂and R₃ are methyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1,1-dimethyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.53. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ismethoxymethyl, and R₃, R₄, R₅ and R₆ are hydrogen;dl-cis-1-methoxymethyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.54. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ismethoxymethyl, and R₃, R₄, R₅ and R₆ are hydrogen;dl-trans-1-methoxymethyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.55. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen,R₃ is isopropyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-isopropyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.56. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ arehydrogen, R₃ is isopropyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-isopropyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.57. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen,R₃ is 2-propynyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-(2-propynyl)-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.58. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ arehydrogen, R₃ is 2-propynyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-(2-propynyl)-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.59. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ are hydrogen,R₃ is allyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-allyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.60. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ and R₂ arehydrogen, R₃ is allyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-allyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.61. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ismethoxy, and R₃, R₄, R₅ and R₆ are hydrogen;dl-cis-1-methoxy-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.62. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ismethoxy, and R₃, R₄, R₅ and R₆ are hydrogen;dl-trans-1-methoxy-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.63. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ismethoxy, R₃ is methyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-methoxy-1-methyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.64. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ismethoxy, R₃ is methyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-methoxy-1-methyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.65. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ishydroxy, and R₃, R₄, R₅ and R₆ are hydrogen;dl-cis-1-hydroxy-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.66. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ishydroxy, and R₃, R₄, R₅ and R₆ are hydrogen;dl-trans-1-hydroxy-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.67. The method according to claim 40 wherein the compound is thecis-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ishydroxy, R₃ is methyl, and R₄, R₅ and R₆ are hydrogen;dl-cis-1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea.68. The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 1, R₁ is hydrogen, R₂ ishydroxy, R₃ is methyl, and R₄, R₅ and R₆ are hydrogen;dl-trans-1-hydroxy-1-methyl-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4yl)urea.69. The method according to claim 40 wherein the compound is thecis-dextrorotatory enantiomorph wherein X is oxygen, n is 2, and R₁, R₂,R₃, R₄, R₅ and R₆ are hydrogen;d-cis-5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-ylurea. 70.The method according to claim 40 wherein the compound is thecis-levorotatory enantiomorph wherein X is oxygen, n is 2, and R₁, R₂,R₃, R₄, R₅ and R₆ are hydrogen;1-cis-5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-ylurea. 71.The method according to claim 40 wherein the compound is the cis-racemicmixture wherein X is oxygen, n is 2, and R₁, R₂, R₃, R₄, R₅ and R₆ arehydrogen;dl-cis-5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-ylurea. 72.The method according to claim 40 wherein the compound is thetrans-dextrorotatory enantiomorph wherein X is oxygen, n is 2, and R₁,R₂, R₃, R₄, R₅ and R₆ are hydrogen;d-trans-5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-ylurea. 73.The method according to claim 40 wherein the compound is thetrans-levorotatory enantiomorph wherein X is oxygen, n is 2, and R₁, R₂,R₃, R₄, R₅ and R₆ are hydrogen;1-trans-5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-ylurea. 74.The method according to claim 40 wherein the compound is thetrans-racemic mixture wherein X is oxygen, n is 2, and R₁, R₂, R₃, R₄,R₅ and R₆ are hydrogen;dl-trans-5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-ylurea.75. An animal feed composition for improving feed efficiency andenhancing the growth rate of poultry, fur-bearing and farm animalscomprising, a nutritionally balanced animal feed containing from 0.0001%to 0.08% by weight of a compound selected from the group consisting ofthose of the formulae: ##STR185## wherein X is oxygen or sulfur; n isthe integer 1 or 2; Y is a divalent radical selected from the groupconsisting of those of the formulae: ##STR186## R₁ is hydrogen or alkylC₁ -C₄ ; R₃ is selected from the group consisting of hydrogen, alkyl C₁-C₄, cycloalkyl C₃ -C₆, allyl, 2-propynyl, benzyl and β-phenethyl; R₄ ishydrogen or alkyl C₁ -C₄ ; R₅ is hydrogen, chloro, bromo or iodo; R₆ ishydrogen or alkyl C₁ -C₄ ; R₂ is selected from the group consisting ofthe substituents listed in the following table:

    ______________________________________                                               hydrogen                                                                      alkyl C.sub.1C.sub.8                                                          cycloalkyl C.sub.3C.sub.6                                                     allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1C.sub.6                                                         allyloxy                                                                      methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                  OCH.sub.2CO.sub.2 H                                                           CO.sub.2 C.sub.2 H.sub.5                                                       ##STR187##                                                                    ##STR188##                                                                    ##STR189##                                                                    ##STR190##                                                                    ##STR191##                                                                    ##STR192##                                                                    ##STR193##                                                            ______________________________________                                    

wherein R is alkyl C₁ -C₄ ; m is 0, 1 or 2, and Q is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR194##
 76. An animal feed premix forenhancing the growth rate of poultry, fur-bearing and farm animalscomprising, from about 70% to 99% by weight of an edible carrier andfrom about 1% to 30% by weight of, a compound selected from the groupconsisting of those of the formulae: ##STR195## wherein X is oxygen orsulfur; n is the integer 1 or 2; Y is a divalent radical selected fromthe group consisting of those of the formulae: ##STR196## R₁ is hydrogenor alkyl C₁ -C₄ ; R₃ is selected from the group consisting of hydrogen,alkyl C₁ -C₄, cycloalkyl C₃ -C₆, allyl, 2-propynyl, benzyl andβ-phenethyl; R₄ is hydrogen or alkyl C₁ -C₄ ; R₅ is hydrogen, chloro,bromo or iodo; R₆ is hydrogen or alkyl C₁ -C₄ ; R₂ is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                               hydrogen                                                                      alkyl C.sub.1C.sub.8                                                          cycloalkyl C.sub.3C.sub.6                                                     allyl                                                                         2-propynyl                                                                    hydroxy                                                                       alkoxy C.sub.1C.sub.6                                                         allyloxy                                                                      methoxymethyl                                                                 phenoxy                                                                       CH.sub.2CH(OR).sub.2                                                          CH.sub.2CF.sub.3                                                              CH.sub.2CN                                                                    NHCO.sub.2 R                                                                  OCH.sub.2CO.sub.2 H                                                           CO.sub.2 C.sub.2 H.sub.5                                                       ##STR197##                                                                    ##STR198##                                                                    ##STR199##                                                                    ##STR200##                                                                    ##STR201##                                                                    ##STR202##                                                                    ##STR203##                                                            ______________________________________                                    

wherein R is alkyl C₁ -C₄, m is 0, 1 or 2, and Q is selected from thegroup consisting of the substituents listed in the following table:

    ______________________________________                                        m = 0           m = 1        m = 2                                            ______________________________________                                        4-nitro         hydrogen     hydrogen                                         3- or 4-methoxy 4-chloro                                                      4-ethoxy        4-methoxy                                                     4-chloro                                                                      4-butoxy                                                                      2,4-dimethyl                                                                  2,4-dichloro                                                                  2,5-dimethoxy                                                                 ______________________________________                                    

and R₂ and R₃ taken together with the associated N(itrogen) is selectedfrom the group consisting of morpholino, piperidino, pyrrolidino,4-(4-methoxyphenyl)piperazino, 1,2,3,4-tetrahydroquinolino and themoiety of the formula: ##STR204##